Pyrrolopyrimidine compounds as inhibitors of CDK4/6

ABSTRACT

The invention is directed to novel pyrrolopyrimidine compounds of formula (1) wherein R 1 , R 2y , R 4 , R 8 -R 11 , A and L are defined herein and to salts, including pharmaceutically acceptable salts thereof. The compounds of the present invention are CDK4/6 inhibitors and could be useful in the treatment of diseases and disorders mediated by CDK4/6, such as cancer, including mantle cell lymphoma, liposarcoma, non small cell lung cancer, melanoma, squamous cell esophageal cancer and breast cancer. The invention is further directed to pharmaceutical compositions comprising a compound of the invention. The invention is still further directed to methods of inhibiting CDK4/6 activity and to the treatment of disorders associated therewith using a compound of the invention or a pharmaceutical composition comprising a compound of the invention.

FIELD OF THE INVENTION

The invention relates to new pyrrolopyrimidine compounds andpharmaceutical compositions thereof, specifically pyrrolopyrimidinecompounds and pharmaceutical compositions thereof which are inhibitorsof CDK4/6. The invention is also directed to the use of these compoundsand compositions in the treatment of hyperproliferative disorders suchas cancer.

BACKGROUND OF THE INVENTION

Mammalian cell cycle progression is a tightly controlled process inwhich transitions through different phases are conducted in a highlyordered manner and guarded by multiple checkpoints. The retinoblastomaprotein (pRb) is the checkpoint protein for the G1 to S phasetransition. pRb associates with a family of E2F transcription factors toprevent their activity in the absence of appropriate growth stimuli (SeeOrtega et al., Biochimica et Biophysica Acta-Reviews on Cancer 2002;1602 (1):73-87; Shapiro, Journal of Clinical Oncology 2006; 24(11):1770-1783). Upon mitogen stimulation, quiescent cells begin theirentry into S phase by newly synthesizing D-cyclins, which are theactivators of cyclin-dependent kinases 4 and 6 (CDK4/6). Once bound bythe cyclins, CDK4/6 deactivate the pRb protein via phosphorylation. Thephosphorylation of pRb releases E2F to direct the transcription of genesrequired for S phase. A full deactivation of pRb requiresphosphorylations by both cyclin D-CDK4/6 and cyclin E-CDK2.Phosphorylations by CDK4/6 at specific sites of pRb (Ser780, Ser795)have been shown to be a prerequisite for cyclin E-CDK2 phosphorylation.(See Lundberg et al., Molecular and Cellular Biology 1998; 18(2):753-761) In addition to D-cyclins, the activity of CDK4/6 isregulated by p16, encoded by INK4a gene, which inhibits the kinaseactivity. (See Kamb et al., Science 1994; 264 (5157):436-440) TheCIP/KIP proteins, which are the inhibitors of cyclin E-CDK2, also bindto cyclin D-CDK4/6 complex, and this results in further activation ofCDK2 by sequestering the CIP/KIP proteins away from their target. (SeeSherr et al., Genes & Development 1999; 13 (12):1501-1512) Therefore,the cyclin D-CDK4/6 is a key enzyme complex that regulates the G1 to Sphase.

The D-cyclin-CDK4/6-INK4a-pRb pathway is universally disrupted to favorcell proliferation in cancer. In a majority of cases (˜80%), cancersmaintain a functional pRb and utilize different mechanisms to increasethe activity of CDK4/6 kinase. (See Ortega et al., Biochimica etBiophysica Acta-Reviews on Cancer 2002; 1602 (1):73-87; Shapiro, Journalof Clinical Oncology 2006; 24 (11):1770-1783)) In Mantle cell lymphoma(MCL), cyclin D1 is translocated to IgH promoter (t11:14) which resultsin constitutive expression of the protein, leading to activation ofCDK416 (See Amin, et al., Archives of Pathology & Laboratory Medicine2003; 127 (4):424-431; Oudat, et al., Modern Pathology 2001; 14(1):175A) This translocation is observed in >90% of the MCL cases andconsidered pathognomic for the disease. The D-cyclin is alsotranslocated in 20% of multiple myelomas. (See Bergsagel et al.,Immunological Reviews 2003; 194 (1):96-104)

In addition to translocation, D-cyclin abundance can also be increasedby amplification or overexpression, and the examples of these can befound in squamous cell esophageal cancer, where a significant portionexhibits cyclin D1 amplification (See Jiang, et al., Cancer Research1992; 52 (10):2980-2983) and in breast cancer, where the overexpressionof cyclin D1 is frequent (See Arnold et al., Journal of ClinicalOncology 2005). The CDK4/6 kinase activity can also be increased byamplification of the CDK4 gene itself and the co-amplifications of CDK4and MDM2 genes are observed in almost all cases of dedifferentiatedliposarcomas. (See Sirvent, et al., American Journal of SurgicalPathology 2007; 31 (10):1476-1489) The genetic inhibitor of CDK4/6 isalso frequently inactivated in cancer to achieve CDK4/6 activation andthe examples of this include non small cell lung cancer, melanoma andpancreatic cancer (Brambilla, et al., Journal of Pathology 1999; 188(4):351-360; Cowgill et al., American Journal of Surgery 2003; 186(3):279-286; Gazzeri, et al., Oncogene 1998; 16 (4):497-504; Kamb etal., Science 1994; 264 (5157):436-440; Ortega et al., Biochimica etBiophysica Acta-Reviews on Cancer 2002; 1602 (1):73-87).

In addition to these genetic defects directly related to theD-cyclin-CDK4/6-INK4a-pRb pathway, the activity of the CDK416 kinasescan also be enhanced by oncogenic aberrations of the mitogen pathwaysthat increase D-cyclin expression. The examples here include EGFRamplifications in non small cell lung cancer (NSCLC), activating K-Rasmutations in pancreatic cancer, V600E B-Raf mutation in melanoma andPTEN inactivation in colon cancer (See Dailey, et al., Cytokine & GrowthFactor Reviews 2005; 16 (2):233-247; Engelman, Nature Reviews Cancer2009; 9 (8):550-562; Garcia-Echeverria, Purinergic Signalling 2009; 5(1):117-125, Gray-Schopfer et al., Cancer and Metastasis Reviews 2005;24 (1):165-183, John, et al., Oncogene 2009; 28:S14-S23, Sharma, et al.,Nature Reviews Cancer 2007; 7 (3):169-181).

Taken together, a large number of human neoplasms achieve enhanced cellproliferation by increasing CDK4/6 activity and a small moleculeinhibitor of these kinases might provide an effective means to treatthese diseases.

Inhibitors of CDKs are known and patent applications have been filed onsuch inhibitors. (See, for example, WO2007/140222)

Thus attempts have been made to prepare compounds that inhibit CDK416activity and a number of such compounds have been disclosed in the art.However, in view of the number of pathological responses that aremediated by CDK4/6, there remains a continuing need for inhibitors ofCDK4/6 which can be used in the treatment of a variety of conditions,including cancer.

SUMMARY OF THE INVENTION

The invention is directed to novel pyrrolopyrimidine compounds offormula (I)

wherein R¹, R^(2Y), R⁴, R⁸-R¹¹, A and L are defined herein and to salts,including pharmaceutically acceptable salts thereof.

The compounds of the present invention are CDK4/6 inhibitors and couldbe useful in the treatment of diseases and disorders mediated by CDK4/6,such as cancer, including mantle cell lymphoma, liposarcoma, non smallcell lung cancer, melanoma, squamous cell esophageal cancer and breastcancer. The invention is further directed to pharmaceutical compositionscomprising a compound of the invention. The invention is still furtherdirected to methods of inhibiting CDK4/6 activity and to the treatmentof disorders associated therewith using a compound of the invention or apharmaceutical composition comprising a compound of the invention.

DETAILED DESCRIPTION OF THE INVENTION

wherein:R¹ is C₃₋₇ alkyl; C₄₋₇ cycloalkyl optionally substituted with onesubstituent selected from the group consisting of C₁₋₆ alkyl and OH;phenyl optionally substituted with one substitutent selected from thegroup consisting of C₁₋₆ alkyl, C(CH₃)₂CN, and OH; piperidinyloptionally substituted with one substituent selected from the groupconsisting of cyclopropyl and C₁₋₆ alkyl; tetrahydropyranyl optionallysubstituted with one substituent selected from the group consisting ofcyclopropyl and C₁₋₆ alkyl; or bicyclo[2.2.1]heptanyl;A is CH or N;R¹¹ is hydrogen or C₁₋₄ alkyl;L is a bond, C(O), or S(O)₂;R^(2Y) is

V is NH or CH₂;X is O or CH₂;W is O or NH;m and n are each independently 1, 2, or 3 provided that m and n are notboth 3;each R^(2Y) is optionally substituted with one to four substituents eachindependently selected from the group consisting of: C₁₋₃ alkyloptionally substituted with one or two substituents each independentlyselected from the group consisting of hydroxy, NH₂, and —S—C₁₋₃ alkyl;CD₃; halo; oxo; C₁₋₃ haloalkyl; hydroxy; NH₂; dimethylamino; benzyl;—C(O)—C₁₋₃alkyl optionally substituted with one or two substituents eachindependently selected from the group consisting of NH₂, —SCH₃ andNHC(O)CH₃; —S(O)₂—C₁₋₄alkyl; pyrrolidinyl-C(O)—; and —C(O)₂—C₁₋₃alkyl;R⁴ is hydrogen, deuterium, or C(R⁵)(R⁶)(R⁷); andR⁵, R⁶, R⁷, R⁸, R⁹ and R¹⁰ are each independently H or deuterium.

One embodiment of the present invention is a compound according toformula (I-B)

whereinL is a bond or C(O);R^(2Y) is

V is NH or CH₂;X is O or CH₂;W is O or NH;m and n are each independently 1, 2, or 3 provided that m and n are notboth 3;each R^(2Y) is optionally substituted with one to four substituents eachindependently selected from the group consisting of: C₁₋₃ alkyloptionally substituted with one or two substituents each independentlyselected from the group consisting of hydroxy, NH₂, and —S—C₁₋₃ alkyl;CD₃; C₁₋₃ haloalkyl; hydroxy; NH₂; dimethylamino; benzyl;—C(O)—C₁₋₃alkyl optionally substituted with one or two substituents eachindependently selected from the group consisting of NH_(2′)—SCH₃ andNHC(O)CH₃; —S(O)₂—C₁₋₄alkyl; pyrrolidinyl-C(O)—; and —C(O)₂—C₁₋₃alkyl;and R¹, R⁴-R¹¹, and A are as defined in formula (I) above.

Another embodiment of the present invention is a compound according toformula (I-C)

wherein:R¹ is cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, each of which isoptionally substituted with one of methyl, ethyl, or OH;A is CH or N;L is a bond, —C(O)—, or S(O)₂—;R^(2Y) is

wherein each R^(2Y) is optionally substituted with one or twosubstituents independently selected from halogen, methyl, ethyl, or oxo;V is NH or CH₂; R⁴ is hydrogen, deuterium, or C(R⁵)(R⁶)(R⁷); and R⁵, R⁶,R⁷, R⁸, R⁹ and R¹⁰ are each independently H or deuterium.

In one embodiment of the present invention L is a bond. In anotherembodiment L is C(O).

In one embodiment A is CH. In another embodiment A is N. Preferably A isCH.

Preferably R¹¹ is hydrogen or methyl. Hydrogen is most preferred.

Preferably R⁴ is C(R⁵)(R⁶)(R⁷) and R⁵, R⁶, R⁷, R⁸, R⁹ and R¹⁰ arehydrogen.

Preferably R¹ is C₄₋₇ cycloalkyl optionally substituted with one C₁₋₆alkyl. In a more preferred embodiment R¹ is optionally substitutedcyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Cyclopentyl ismost preferred. Unsubstituted cyclobutyl, cyclopentyl, cyclohexyl, andcycloheptyl are also preferred.

In another embodiment of the invention R^(2Y) is:

In another embodiment R^(2Y) is:

In another embodiment R^(2Y) is:

In another embodiment R^(2Y) is

In another embodiment R^(2Y) is

In another embodiment R^(2Y) is

In another embodiment R^(2Y) is

In another embodiment R^(2Y) is

In a preferred embodiment R^(2Y) is

In a preferred embodiment R^(2Y) is

optionally substituted with one C₁₋₃alkyl.

In a preferred embodiment R^(2Y) is

optionally substituted with one C₁₋₃alkyl.

In a preferred embodiment R^(2Y) is

In a preferred embodiment R^(2Y) is

optionally substituted with one C₁₋₃alkyl.

In a preferred embodiment R^(2Y) is

optionally substituted with one C₁₋₃alkyl.

In a preferred embodiment R^(2Y) is

In a preferred embodiment R^(2Y) is

Preferably R^(2Y) is unsubstituted.

Specific compounds of the present invention include:

-   Cyclopentyl-2-(5-(9-hydroxy-1,5,7-trimethyl-3,7-diazabicyclo[3.3.1]nonane-3-carbonyl)pyridin-2-ylamino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide;-   2-(6-(2,6-Diazaspiro[3.3]heptane-2-carbonyl)pyridin-2-ylamino)-7-cyclopentyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide;-   7-(4-tert-Butyl-phenyl)-2-[5-(3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic    acid dimethylamide;-   7-Cyclopentyl-2-[5-(4-oxo-3,9-diaza-bicyclo[4.2.1]non-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic    acid dimethylamide;-   7-Cyclopentyl-2-[5-((1R,6S)-4-oxo-3,9-diaza-bicyclo[4.2.1]non-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic    acid dimethylamide;-   7-Cyclopentyl-2-[5-(3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic    acid dimethylamide;-   7-Cycloheptyl-2-[5-(2,5-diaza-bicyclo[2.2.1]heptane-2-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic    acid dimethylamide;-   7-Cyclopentyl-2-[5-(3,8-diaza-bicyclo[3.2.1]octane-8-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic    acid dimethylamide;-   2-(5-(2,7-diazaspiro[3.5]nonane-7-carbonyl)pyridin-2-ylamino)-7-cycloheptyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide;-   7-cyclopentyl-2-[5-(8-methyl-3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic    acid dimethylamide;-   7-Cyclopentyl-2-[5-((S,S)-2,5-diaza-bicyclo[2.2.1]heptane-2-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic    acid methylamide;-   7-(3-tert-Butyl-phenyl)-2-[5-(3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic    acid dimethylamide;-   2-(5-((1R,5S)-3-oxa-7,9-diazabicyclo[3.3.1]nonane-9-carbonyl)pyridin-2-ylamino)-7-cyclopentyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide;-   7-[4-(Cyano-dimethyl-methyl)-phenyl]-2-[5-(3,8-diaza-bicyclo[3.2.1]octane-8-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic    acid dimethylamide;-   7-Cyclopentyl-2-[5-((1S,6R)-3,9-diaza-bicyclo[4.2.1]nonane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic    acid dimethylamide;-   7-Cyclopentyl-2-[5-((1R,6S)-3,9-diaza-bicyclo[4.2.1]nonane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic    acid dimethylamide;-   7-Cyclopentyl-2-[5-(3,6-diaza-bicyclo[3.2.1]octane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic    acid dimethylamide;-   7-Cyclopentyl-2-[5-(hexahydro-pyrrolo[1,2-a]pyrazine-2-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic    acid dimethylamide;-   7-cyclopentyl-N,N-dimethyl-2-(5-(5′-oxo-8-azaspiro[bicyclo[3.2.1]octane-3,3′-pyrrolidine]-1′-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide;-   7-Cyclopentyl-2[5-(1-oxo-hexahydro-pyrrolo[1,2-a]pyrazin-2-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic    acid dimethylamide;-   7-cyclopentyl-N,N-dimethyl-2-(5-(2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide;-   7-Cyclopentyl-2-[5-((1S,6R)-4-oxo-3,9-diaza-bicyclo[4.2.1]non-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic    acid dimethylamide;-   2-[5-(4-Oxo-3,9-diaza-bicyclo[4.2.1]non-3-yl)-pyridin-2-ylamino]-7-phenyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic    acid dimethylamide; and-   7-cyclohexyl-N,N-dimethyl-2-(5-(4-oxo-3,9-diazabicyclo[4.2.1]nonan-3-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide.

Preferred compounds of the present invention include compounds selectedfrom the group consisting of:

-   7-Cyclopentyl-2-[5-(3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic    acid dimethylamide-   7-Cyclopentyl-2-[5-((S,S)-2,5-diaza-bicyclo[2.2.1]heptane-2-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic    acid dimethylamide-   7-Cyclopentyl-2-[5-((1R,6S)-4-oxo-3,9-diaza-bicyclo[4.2.1]non-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic    acid dimethylamide-   7-Cyclopentyl-2-[5-((1S,5S)-3,6-diaza-bicyclo[3.2.1]octane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic    acid dimethylamide;-   7-Cyclobutyl-2-[5-((1S,6R)-4-oxo-3,9-diaza-bicyclo[4.2.1]non-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic    acid dimethylamide-   7-Cyclohexyl-2-[5-((1R,6S)-4-oxo-3,9-diaza-bicyclo[4.2.1]non-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic    acid dimethylamide-   7-Cyclopentyl-2-[5-(3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl)-6-methyl-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic    acid dimethylamide;-   7-Cyclopentyl-2-[5-(3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl)-4-methyl-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic    acid dimethylamide;-   7-Cyclopentyl-2-[5-(3,9-diaza-bicyclo[3.3.1]nonane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic    acid dimethylamide;-   7-cyclopentyl-N,N-dimethyl-2-(5-(3-oxo-1,4-diazabicyclo[3.2.2]nonan-4-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide;    and-   7-cyclopentyl-N,N-dimethyl-2-(5-((1R,6S)-9-methyl-4-oxo-3,9-diazabicyclo[4.2.1]nonan-3-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide.

Preferred compounds of the present invention include compounds selectedfrom the group consisting of:

-   7-cyclopentyl-N,N-dimethyl-2-(5-((3aS,6aR)-1-oxohexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide;-   7-cyclopentyl-N,N-dimethyl-2-(5-((3aR,6aS)-1-oxohexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide;-   7-cycloheptyl-N,N-dimethyl-2-(5-(cis-6-oxotetrahydro-1H-pyrrolo[3,4-c]pyridin-5(6H,7H,7aH)-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide;-   7-cyclopentyl-N,N-dimethyl-2-(5-(cis-6-oxotetrahydro-1H-pyrrolo[3,4-c]pyridin-5(6H,7H,7aH)-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide;-   7-cyclopentyl-N,N-dimethyl-2-(5-(cis-6-oxotetrahydro-1H-pyrrolo[3,4-c]pyridin-5(6H,7H,7aH)-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide;    and-   7-cyclopentyl-N,N-dimethyl-2-(5-((3aR,6aS)-5-methyl-1-oxohexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide.

Preferred compounds of the present invention include compounds selectedfrom the group consisting of:

-   7-cyclopentyl-N,N-dimethyl-2-(5-((1R,3r,5S)-2′-oxo-8-azaspiro[bicyclo[3.2.1]octane-3,5′-oxazolidine]-3′-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide;-   7-cyclopentyl-N,N-dimethyl-2-(5-(2-oxo-1-oxa-3,8-diazaspiro[4.6]undecan-3-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide;-   7-cyclopentyl-N,N-dimethyl-2-(5-(2-oxo-1-oxa-3,7-diazaspiro[4.5]decan-3-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide;-   7-Cyclopentyl-2-[5-((S)-2-oxo-1-oxa-3,7-diaza-spiro[4.5]dec-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic    acid dimethylamide; and-   7-Cyclopentyl-2-[5-((R)-2-oxo-1-oxa-3,7-diaza-spiro[4.5]dec-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic    acid dimethylamide.    Terms and Definitions

As used herein, the term “alkyl” refers to a fully saturated branched orunbranched hydrocarbon moiety having 1 to 6 carbon atoms (C₁₋₆ alkyl), 3to 7 carbon atoms (C₃₋₇ alkyl), 1 to 4 carbon atoms (C₁₋₄ alkyl), or 1to 3 carbon atoms (C₁₋₃ alkyl). Representative examples of alkylinclude, but are not limited to, methyl, ethyl, n-propyl, i-propyl,n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, 1-methylbutyl,2-methylbutyl, 3-methylbutyl, 3,3-dimethylpropyl, hexyl, 2-methylpentyl,and the like.

As used herein, the term “cycloalkyl” refers to nonaromatic carbocyclicrings that are either partially or fully hydrogenated and may exist as asingle ring, bicyclic ring, tricyclic ring, or a spiral ring. Unlessspecified otherwise, cycloalkyl refers to cyclic hydrocarbon groups of3-14 carbon atoms. Cycloalkyl groups also refer to cyclic hydrocarbongroups having between 3 to 9 ring carbon atoms, or between 4 and 7 ringcarbon atoms Exemplary monocyclic hydrocarbon groups include, but arenot limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl,cyclohexyl, cyclohexenyl, cycloheptyl and the like. Exemplary bicyclichydrocarbon groups include bornyl, indyl, hexahydroindyl,tetrahydronaphthyl, decahydronaphthyl, bicyclo[2.1.1]hexyl,bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl,6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl,bicyclo[2.2.2]octyl and the like. Exemplary tricyclic hydrocarbon groupsinclude adamantyl and the like.

“Deuterium”, or “D”, or “d” refers to an isotope of hydrogen whosenucleus contains one proton and one neutron. When a particular positionis designated as having deuterium, it is understood that the abundanceof deuterium at that position is greater than the natural abundance ofdeuterium (typically 0.015%). Unless otherwise stated, when a positionis designated specifically as “D” or “deuterium”, the position isunderstood to have deuterium at an abundance that is greater than thenatural abundance of deuterium.

As used herein, the term “halogen” or “halo” refers to fluoro, chloro,bromo, and Iodo.

As used herein, the term “haloalkyl” refers to an alkyl group wherein atleast one hydrogen atom attached to a carbon atom of the alkyl group isreplaced with halo, preferably fluoro. Examples of haloalkyl groupsinclude mono-, di-, and tri-fluoromethyl, mono-, di-, andtri-chloromethyl, mono-, di-, tri-, tetra, and penta-fluoroethyl, andmono-, di-, tri-, tetra-, and penta-chloroethyl.

As used herein, the term “optionally substituted” indicates that a groupsuch as alkyl, cycloalkyl, or a specific R group may be unsubstituted orsubstituted with one or more substituents as defined herein. The term“substituted” in reference to a group indicates that a hydrogen atomattached to an atom within the group is replaced. It would be understoodthat the term “substituted” includes the implicit provision that suchsubstitution be in accordance with the permitted valance of thesubstituted atom and the substituent; and that the substitution resultsin a stable compound (i.e. one that does not spontaneously undergotransformations such as by rearrangement, cyclization, or elimination.In certain embodiments, a single atom may be substituted with more thanone substituent so long as such substitution is in accordance with thepermitted valance of the atom. Suitable substituents are defined hereinfor each substituted or optionally substituted group.

The term “compounds of the present invention” (unless specificallyidentified otherwise) refer to compounds of Formula (I) and saltsthereof, including pharmaceutically acceptable salts of the compounds,as well as, all stereoisomers (including diastereoisomers andenantiomers), tautomers and isotopically labeled compounds. Solvates andhydrates are generally considered pharmaceutical compositions of thecompounds of the present invention.

As used herein the symbols and conventions used in these processes,schemes, and examples are consistent with those used in the contemporaryscientific literature, for example the Journal of the American ChemicalSociety or the Journal of Biological Chemistry. Unless otherwise noted,all starting materials were obtained from commercial suppliers and usedwithout further purification. Specifically the following abbreviationsmay be used in the examples and throughout the specification.

ACN acetonitrile

AcOH acetic acid

aq. aqueous

BnBr benzylbromide

boc tert-butoxycarbonyl

C Celsius

cat. catalytic

CDI cabonyldiimidazole

CSA camphorsulfonic acid

conc. concentrated

Cs₂CO₃ cesium carbonate

Da Daltons

deg degrees

DIBAL, DIBAL-H diisobutylaluminum hydride

DIPEA diisopropylethylamine

DIPC N,N′-diisopropylcarbodiimide

DMF N,N-dimethylformamide

DMI 1,3 dimethyl-2-imidazolidinone

DMP Dess-Martin periodinane

DCC N,N-dicyclohexylcarbodiimide

DCE dichloroethane

DCM dichloromethane

DMAP 4-dimethylaminopyridine

DMSO dimethylsulfoxide

EtOAc ethyl acetate

EtOH ethanol

eq equivalents

g gas

h hours

HATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate

HMPA hexamethlphosphoramide

hep heptane

HCl hydrochloric acid

inh. inhibition

imid. Imidazole

K Kelvin

KHMDS potassium hexamethyldisilylazide

K₂CO₃ potassium carbonate

LDA lithiumdiisopropylamine

LiBH₄ lithium borohydride

LHMDS lithiumhexamethyldisilylazide

LC liquid chromatography

LC/MS liquid chromatography mass spectrum

M molar

MeCN acetonitrile

MeOH methanol

MgSO₄ magnesium sulfate

MHz megahertz

min minutes

mol. sieves molecular sieves

NaBH₄ sodium borohydride

N normal

NMR nuclear magnetic resonance

Pd/C palladium on carbon

PEG(750) O-(2-aminoethyl)-O′-methyl polyethylene glycol 750;NH₂(CH₂CH₂O)_(n)CH₃; CAS# [80506-64-5]; Fluka 07964; AVERAGE MW=750

PS polystyrene

Py pyridine

PPM parts per million

RP reverse phase

RT room temperature

Rt retention time

s solid

satd. saturated

TBS tert-butyldimethylsilyl

TMS trimethylsilyl

TBAF tetrabutylammonum fluoride

TBTU O-benzotriazol-1-yl-N,N,N,N′-tetramethyluronium tetrafluoroborate

TLC thin-layer chromatography

TEA triethylamine

TFA trifluoroacetic acid

THF tetrahydrofuran

h hours

min minutes

m/z mass to charge

MS mass spectrum

NMR nuclear magnetic resonance

The skilled artisan will appreciate that salts, includingpharmaceutically acceptable salts of the compounds of formula (I) may beprepared. As used herein, the terms “salt” or “salts” refers to an acidaddition or base addition salt of a compound of the invention. The term“pharmaceutically acceptable salts” refers to salts that retain thebiological effectiveness and properties of the compounds of thisinvention and, which typically are not biologically or otherwiseundesirable. Accordingly the invention is further directed to salts,preferably pharmaceutically acceptable salts, of the compounds offormula (I).

Pharmaceutically acceptable acid addition salts can be formed withinorganic acids and organic acids, e.g., acetate, aspartate, benzoate,besylate, bromide/hydrobromide, bicarbonate/carbonate,bisulfate/sulfate, camphorsulformate, chloride/hydrochloride,chlortheophyllonate, citrate, ethandisulfonate, fumarate, gluceptate,gluconate, glucuronate, hippurate, hydroiodide/iodide, isethionate,lactate, lactobionate, laurylsulfate, malate, maleate, malonate,mandelate, mesylate, methylsulphate, naphthoate, napsylate, nicotinate,nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate,phosphate/hydrogen phosphate/dihydrogen phosphate, polygalacturonate,propionate, stearate, succinate, sulfosalicylate, tartrate, tosylate andtrifluoroacetate salts.

Inorganic acids from which salts can be derived include, for example,hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like.

Organic acids from which salts can be derived include, for example,acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid,malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid,benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,toluenesulfonic acid, sulfosalicylic acid, and the like.

Pharmaceutically acceptable base addition salts can be formed withinorganic and organic bases.

Inorganic bases from which salts can be derived include, for example,ammonium salts and metals from columns I to XII of the periodic table.In certain embodiments, the salts are derived from sodium, potassium,ammonium, calcium, magnesium, iron, silver, zinc, and copper;particularly suitable salts include ammonium, potassium, sodium, calciumand magnesium salts.

Organic bases from which salts can be derived include, for example,primary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines, basic ionexchange resins, and the like. Certain organic amines includeisopropylamine, benzathine, cholinate, diethanolamine, diethylamine,lysine, meglumine, piperazine and tromethamine.

The pharmaceutically acceptable salts of the present invention can besynthesized from a parent compound, a basic or acidic moiety, byconventional chemical methods. Generally, such salts can be prepared byreacting free acid forms of these compounds with a stoichiometric amountof the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate,bicarbonate or the like), or by reacting free base forms of thesecompounds with a stoichiometric amount of the appropriate acid. Suchreactions are typically carried out in water or in an organic solvent,or in a mixture of the two. Generally, use of non-aqueous media likeether, ethyl acetate, ethanol, isopropanol, or acetonitrile isdesirable, where practicable. Lists of additional suitable salts can befound, e.g., in “Remington's Pharmaceutical Sciences”, 20th ed., MackPublishing Company, Easton, Pa., (1985); and in “Handbook ofPharmaceutical Salts: Properties, Selection, and Use” by Stahl andWermuth (Wiley-VCH, Weinheim, Germany, 2002).

The compounds according to formula (I) may contain one or moreasymmetric centers (also referred to as a chiral center) and may,therefore, exist as individual enantiomers, diastereomers, or otherstereoisomeric forms, or as mixtures thereof. Chiral centers, such aschiral carbon atoms, may also be present in a substituent, such as analkyl group. Where the stereochemistry of a chiral center present informula (I), or in any chemical structure illustrated herein, is notspecified, the structure is intended to encompass any stereoisomer ormixtures thereof. Thus, the compounds according to formula (I)containing one or more chiral centers may be used as racemic mixtures,enantiomerically enriched mixtures, or as enantiomerically pureindividual stereoisomers.

As used herein, the term “isomers” refers to different compounds thathave the same molecular formula but differ in arrangement andconfiguration of the atoms. Also as used herein, the term “an opticalisomer” or “a stereoisomer” refers to any of the various stereo isomericconfigurations which may exist for a given compound of the presentinvention and includes geometric isomers. It is understood that asubstituent may be attached at a chiral center of a carbon atom.Therefore, the invention includes enantiomers, diastereomers orracemates of the compound. “Enantiomers” are a pair of stereoisomersthat are non-superimposable mirror images of each other. A 1:1 mixtureof a pair of enantiomers is a “racemic” mixture. The term is used todesignate a racemic mixture where appropriate. “Diastereoisomers” arestereoisomers that have at least two asymmetric atoms, but which are notmirror-images of each other. The absolute stereochemistry is specifiedaccording to the Cahn-IngoId-Prelog R-S system. When a compound is apure enantiomer the stereochemistry at each chiral carbon may bespecified by either R or S. Stereochemistry can also be specified byusing a heavy wedge-shaped bond or a hatched line, when the chemicalstructure of a compound or substituent is drawn. Resolved compoundswhose absolute configuration is unknown can be designated (+) or (−)depending on the direction (dextro- or levorotatory) which they rotateplane polarized light at the wavelength of the sodium D line. Certaincompounds described herein contain one or more asymmetric centers oraxes and may thus give rise to enantiomers, diastereomers, and otherstereoisomeric forms that may be defined, in terms of absolutestereochemistry, as (R)- or (S)-. The present invention is meant toinclude all such possible isomers, including racemic mixtures, opticallypure forms and intermediate mixtures.

Optically active (R)- and (S)-isomers may be prepared using chiralsynthons or chiral reagents, or resolved using conventional techniques.Any resulting racemates of final products or intermediates can beresolved into the optical antipodes by known methods, e.g., byseparation of the diastereomeric salts thereof, obtained with anoptically active acid or base, and liberating the optically activeacidic or basic compound. In particular, a basic moiety may thus beemployed to resolve the compounds of the present invention into theiroptical antipodes, e.g., by fractional crystallization of a salt formedwith an optically active acid, e.g., tartaric acid, dibenzoyl tartaricacid, diacetyl tartaric acid, di-O,O′-p-toluoyl tartaric acid, mandelicacid, malic acid or camphor-10-sulfonic acid. Racemic products can alsobe resolved by chiral chromatography, e.g., high pressure liquidchromatography (HPLC) using a chiral adsorbent.

If a compound of the invention contains a double bond, the substituentmay be E or Z configuration. If the compound contains a disubstitutedcycloalkyl, the cycloalkyl substituent may have a cis- ortrans-configuration. All tautomeric forms are also intended to beincluded.

Any asymmetric atom (e.g., carbon or the like) of the compound(s) of thepresent invention can be present in racemic or enantiomericallyenriched, for example the (R)-, (S)- or (R,S)-configuration. In certainembodiments, each asymmetric atom has at least 50% enantiomeric excess,at least 60% enantiomeric excess, at least 70% enantiomeric excess, atleast 80% enantiomeric excess, at least 90% enantiomeric excess, atleast 95% enantiomeric excess, or at least 99% enantiomeric excess inthe (R)- or (S)-configuration. Substituents at atoms with unsaturatedbonds may, if possible, be present in cis-(Z)- or trans-(E)-form.

Any resulting mixtures of isomers can be separated on the basis of thephysicochemical differences of the constituents, into the pure orsubstantially pure geometric or optical isomers, diastereomers,racemates, for example, by chromatography and/or fractionalcrystallization.

Substitution with heavier isotopes, particularly deuterium (i.e., ²H orD) may afford certain therapeutic advantages resulting from greatermetabolic stability, for example increased in vivo half-life or reduceddosage requirements or an improvement in therapeutic index. It isunderstood that deuterium in this context is regarded as a substituentof the compounds of the present invention. The concentration of such aheavier isotope, specifically deuterium, may be defined by the isotopicenrichment factor. The term “isotopic enrichment factor” as used hereinmeans the ratio between the isotopic abundance and the natural abundanceof a specified isotope. If a substituent in a compound of this inventionis denoted deuterium, such compound has an isotopic enrichment factorfor each designated deuterium atom of at least 3500 (52.5% deuteriumincorporation at each designated deuterium atom), at least 4000 (60%deuterium incorporation), at least 4500 (67.5% deuterium incorporation),at least 5000 (75% deuterium incorporation), at least 5500 (82.5%deuterium incorporation), at least 6000 (90% deuterium incorporation),at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97%deuterium incorporation), at least 6600 (99% deuterium incorporation),or at least 6633.3 (99.5% deuterium incorporation).

In addition to the deuterium-containing compounds presently exemplified,any formula given herein is also intended to represent unlabeled formsas well as isotopically labeled forms of the compounds. Isotopicallylabeled compounds have structures depicted by the formulas given hereinexcept that one or more atoms are replaced by an atom having a selectedatomic mass or mass number. Examples of isotopes that can beincorporated into compounds of the invention include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine,such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸F ³¹P, ³²P, ³⁵S, ³⁶Cl, ¹²⁵Irespectively. The invention includes various isotopically labeledcompounds as defined herein, for example those into which radioactiveisotopes, such as ³H, ¹³C, and ¹⁴C, are present. Such isotopicallylabeled compounds are useful in metabolic studies (with ¹⁴C), reactionkinetic studies (with, for example ²H or ³H), detection or imagingtechniques, such as positron emission tomography (PET) or single-photonemission computed tomography (SPECT) including drug or substrate tissuedistribution assays, or in radioactive treatment of patients. Inparticular, an ¹⁸F or labeled compound may be particularly desirable forPET or SPECT studies. Isotopically labeled compounds of this inventionand prodrugs thereof can generally be prepared by carrying out theprocedures disclosed in the schemes or in the examples and preparationsdescribed below by substituting a readily available isotopically labeledreagent for a non-isotopically labeled reagent.

Isotopically-labeled compounds of the present invention can generally beprepared by conventional techniques known to those skilled in the art orby processes analogous to those described in the accompanying Examplesand Compound Preparations using an appropriate isotopically-labeledreagents in place of the non-labeled reagent previously employed.

Furthermore, the compounds of the present invention, including theirsalts, can also be obtained in the form of their hydrates, or includeother solvents used for their crystallization. The compounds of thepresent invention may inherently or by design form solvates withpharmaceutically acceptable solvents (including water); therefore, it isintended that the invention embrace both solvated and unsolvated forms.The term “solvate” refers to a molecular complex of a compound of thepresent invention (including pharmaceutically acceptable salts thereof)with one or more solvent molecules. Such solvent molecules are thosecommonly used in the pharmaceutical art, which are known to be innocuousto the recipient, e.g., water, ethanol, and the like. The term “hydrate”refers to the complex where the solvent molecule is water. Moreover,pharmaceutically acceptable solvates in accordance with the inventioninclude those wherein the solvent of crystallization may be isotopicallysubstituted, e.g. D₂O, d₆-acetone, d₆-DMSO.

The present invention also provides pro-drugs of the compounds of thepresent invention that converts in vivo to the compounds of the presentinvention. A pro-drug is an active or inactive compound that is modifiedchemically through in vivo physiological action, such as hydrolysis,metabolism and the like, into a compound of this invention followingadministration of the prodrug to a subject. The suitability andtechniques involved in making and using pro-drugs are well known bythose skilled in the art. Prodrugs can be conceptually divided into twonon-exclusive categories, bioprecursor prodrugs and carrier prodrugs.See The Practice of Medicinal Chemistry, Ch. 31-32 (Ed. Wermuth,Academic Press, San Diego, Calif., 2001). Generally, bioprecursorprodrugs are compounds, which are inactive or have low activity comparedto the corresponding active drug compound, that contain one or moreprotective groups and are converted to an active form by metabolism orsolvolysis. Both the active drug form and any released metabolicproducts should have acceptably low toxicity.

Carrier prodrugs are drug compounds that contain a transport moiety,e.g., that improve uptake and/or localized delivery to a site(s) ofaction. Desirably for such a carrier prodrug, the linkage between thedrug moiety and the transport moiety is a covalent bond, the prodrug isinactive or less active than the drug compound, and any releasedtransport moiety is acceptably non-toxic. For prodrugs where thetransport moiety is intended to enhance uptake, typically the release ofthe transport moiety should be rapid. In other cases, it is desirable toutilize a moiety that provides slow release, e.g., certain polymers orother moieties, such as cyclodextrins. Carrier prodrugs can, forexample, be used to improve one or more of the following properties:increased lipophilicity, increased duration of pharmacological effects,increased site-specificity, decreased toxicity and adverse reactions,and/or improvement in drug formulation (e.g., stability, watersolubility, suppression of an undesirable organoleptic or physiochemicalproperty). For example, lipophilicity can be increased by esterificationof (a) hydroxyl groups with lipophilic carboxylic acids (e.g., acarboxylic acid having at least one lipophilic moiety), or (b)carboxylic acid groups with lipophilic alcohols (e.g., an alcohol havingat least one lipophilic moiety, for example aliphatic alcohols).

Exemplary prodrugs are, e.g., esters of free carboxylic acids and S-acylderivatives of thiols and O-acyl derivatives of alcohols or phenols,wherein acyl has a meaning as defined herein. Suitable prodrugs areoften pharmaceutically acceptable ester derivatives convertible bysolvolysis under physiological conditions to the parent carboxylic acid,e.g., lower alkyl esters, cycloalkyl esters, lower alkenyl esters,benzyl esters, mono- or di-substituted lower alkyl esters, such as the□-(amino, mono- or di-lower alkylamino, carboxy, loweralkoxycarbonyl)-lower alkyl esters, the □-(lower alkanoyloxy, loweralkoxycarbonyl or di-lower alkylaminocarbonyl)-lower alkyl esters, suchas the pivaloyloxymethyl ester and the like conventionally used in theart. In addition, amines have been masked as arylcarbonyloxymethylsubstituted derivatives which are cleaved by esterases in vivo releasingthe free drug and formaldehyde (Bundgaard, J. Med. Chem. 2503 (1989)).Moreover, drugs containing an acidic NH group, such as imidazole, imide,indole and the like, have been masked with N-acyloxymethyl groups(Bundgaard, Design of Prodrugs, Elsevier (1985)). Hydroxy groups havebeen masked as esters and ethers. EP 039,051 (Sloan and Little)discloses Mannich-base hydroxamic acid prodrugs, their preparation anduse.

Compositions

In another aspect, the present invention provides a pharmaceuticalcomposition comprising a compound of formula (I) or a pharmaceuticallyacceptable salt thereof and a pharmaceutically acceptable carrier. Thepharmaceutical composition can be formulated for particular routes ofadministration such as oral administration, parenteral administration,and rectal administration, etc. In addition, the pharmaceuticalcompositions of the present invention can be made up in a solid form(including without limitation capsules, tablets, pills, granules,powders or suppositories), or in a liquid form (including withoutlimitation solutions, suspensions or emulsions). The pharmaceuticalcompositions can be subjected to conventional pharmaceutical operationssuch as sterilization and/or can contain conventional inert diluents,lubricating agents, or buffering agents, as well as adjuvants, such aspreservatives, stabilizers, wetting agents, emulsifiers and buffers,etc.

Typically, the pharmaceutical compositions are tablets or gelatincapsules comprising the active ingredient together with a) diluents,e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/orglycine; b) lubricants, e.g., silica, talcum, stearic acid, itsmagnesium or calcium salt and/or polyethyleneglycol; for tablets also c)binders, e.g., magnesium aluminum silicate, starch paste, gelatin,tragacanth, methylcellulose, sodium carboxymethylcellulose and/orpolyvinylpyrrolidone; if desired; d) disintegrants, e.g., starches,agar, alginic acid or its sodium salt, or effervescent mixtures; and/ore) absorbents, colorants, flavors and sweeteners.

Tablets may be either film coated or enteric coated according to methodsknown in the art. Suitable compositions for oral administration includean effective amount of a compound of the invention in the form oftablets, lozenges, aqueous or oily suspensions, dispersible powders orgranules, emulsion, hard or soft capsules, or syrups or elixirs.Compositions intended for oral use are prepared according to any methodknown in the art for the manufacture of pharmaceutical compositions andsuch compositions can contain one or more agents selected from the groupconsisting of sweetening agents, flavoring agents, coloring agents andpreserving agents in order to provide pharmaceutically elegant andpalatable preparations. Tablets may contain the active ingredient inadmixture with nontoxic pharmaceutically acceptable excipients which aresuitable for the manufacture of tablets. These excipients are, forexample, inert diluents, such as calcium carbonate, sodium carbonate,lactose, calcium phosphate or sodium phosphate; granulating anddisintegrating agents, for example, corn starch, or alginic acid;binding agents, for example, starch, gelatin or acacia; and lubricatingagents, for example magnesium stearate, stearic acid or talc. Thetablets are uncoated or coated by known techniques to delaydisintegration and absorption in the gastrointestinal tract and therebyprovide a sustained action over a longer period. For example, a timedelay material such as glyceryl monostearate or glyceryl distearate canbe employed. Formulations for oral use can be presented as hard gelatincapsules wherein the active ingredient is mixed with an inert soliddiluent, for example, calcium carbonate, calcium phosphate or kaolin, oras soft gelatin capsules wherein the active ingredient is mixed withwater or an oil medium, for example, peanut oil, liquid paraffin orolive oil.

Certain injectable compositions are aqueous isotonic solutions orsuspensions, and suppositories are advantageously prepared from fattyemulsions or suspensions. Said compositions may be sterilized and/orcontain adjuvants, such as preserving, stabilizing, wetting oremulsifying agents, solution promoters, salts for regulating the osmoticpressure and/or buffers. In addition, they may also contain othertherapeutically valuable substances. Said compositions are preparedaccording to conventional mixing, granulating or coating methods,respectively, and contain about 0.1-75%, or contain about 1-50%, of theactive ingredient.

Suitable compositions for transdermal application include an effectiveamount of a compound of the invention with a suitable carrier. Carrierssuitable for transdermal delivery include absorbable pharmacologicallyacceptable solvents to assist passage through the skin of the host. Forexample, transdermal devices are in the form of a bandage comprising abacking member, a reservoir containing the compound optionally withcarriers, optionally a rate controlling barrier to deliver the compoundof the skin of the host at a controlled and predetermined rate over aprolonged period of time, and means to secure the device to the skin.

Suitable compositions for topical application, e.g., to the skin andeyes, include aqueous solutions, suspensions, ointments, creams, gels orsprayable formulations, e.g., for delivery by aerosol or the like. Suchtopical delivery systems will in particular be appropriate for dermalapplication, e.g., for the treatment of skin cancer, e.g., forprophylactic use in sun creams, lotions, sprays and the like. They arethus particularly suited for use in topical, including cosmetic,formulations well-known in the art. Such may contain solubilizers,stabilizers, tonicity enhancing agents, buffers and preservatives.

As used herein a topical application may also pertain to an inhalationor to an intranasal application. They may be conveniently delivered inthe form of a dry powder (either alone, as a mixture, for example a dryblend with lactose, or a mixed component particle, for example withphospholipids) from a dry powder inhaler or an aerosol spraypresentation from a pressurised container, pump, spray, atomizer ornebuliser, with or without the use of a suitable propellant.

The present invention further provides anhydrous pharmaceuticalcompositions and dosage forms comprising the compounds of the presentinvention as active ingredients, since water may facilitate thedegradation of certain compounds. Anhydrous pharmaceutical compositionsand dosage forms of the invention can be prepared using anhydrous or lowmoisture containing ingredients and low moisture or low humidityconditions. An anhydrous pharmaceutical composition may be prepared andstored such that its anhydrous nature is maintained. Accordingly,anhydrous compositions are packaged using materials known to preventexposure to water such that they can be included in suitable formularykits. Examples of suitable packaging include, but are not limited to,hermetically sealed foils, plastics, unit dose containers (e.g., vials),blister packs, and strip packs.

The invention further provides pharmaceutical compositions and dosageforms that comprise one or more agents that reduce the rate by which thecompound of the present invention as an active ingredient willdecompose. Such agents, which are referred to herein as “stabilizers,”include, but are not limited to, antioxidants such as ascorbic acid, pHbuffers, or salt buffers, etc.

Methods of Use

The compounds of the present invention inhibitors of CDK4/6 andtherefore may be capable of treating diseases wherein the underlyingpathology is (at least in part) mediated by CDK4/6. Such diseasesinclude cancer and other diseases in which there is a disorder of cellproliferation, apoptosis, or differentiation.

Thus the compounds of the present invention may be useful in thetreatment of RB+ve (retinoblastoma protein positive) tumours, includingtumours harbouring mutations in Ras, Raf, Growth Factor Receptors orover-expression of Growth Factor Receptors. The compounds of the presentinvention may also be useful in the treatment of tumours withamplifications of CDK4 and CDK6 genes as well as, tumoursover-expressing cyclin partners of the cyclin dependent kinases. Thecompounds of the present invention may also be useful in the treatmentof RB-ve tumours.

The compounds of the present invention may also be useful in thetreatment tumours with genetic aberrations that activate the CDK4/6kinase activity. These include, but are not limited to, cancers withD-cyclin translocations such as mantle cell lymphoma and multiplemyeloma, D-cyclin amplifications such as breast cancer and squamous cellesophageal cancer, CDK4 amplifications such as liposarcoma, CDK6amplifications or overexpressions such as T-cell lymphoma and p16inactivation such as melanoma, non-small cell lung cancer and pancreaticcancer.

The compounds of the present invention may be useful in the treatment ofcancers that have genetic aberrations in the upstream regulators ofD-cyclins, where the defect results in an increase of D-cyclinsabundance, can also be considered for treatment. These include, but arenot limited to, acute myeloid leukemia with FLT3 activation, breastcancers with Her2/neu overexpression, ER dependency or triple negativephenotype, colon cancers with activating mutations of the MAPK, PI3K orWNT pathway, melanomas with activating mutations of MAPK pathway, nonsmall cell lung cancers with activating aberrations of EGFR pathway andpancreatic cancers with activating aberrations of MAPK pathway includingK-ras mutations.

Examples of cancers which may be treated with a compound of the presentinvention include but are not limited to, carcinoma, for example acarcinoma of the bladder, breast, colon (e.g. colorectal carcinomas suchas colon adenocarcinoma and colon adenoma), kidney, epidermis, liver,Iung (e.g. adenocarcinoma, small cell lung cancer and non-small celllung carcinomas), oesophagus, gall bladder, ovary, pancreas (e.g.exocrine pancreatic carcinoma), stomach, cervix, thyroid, nose, head andneck, prostate, and skin (e.g. squamous cell carcinoma). Other examplesof cancers that may be treated with a compound of the present inventioninclude hematopoletic tumours of lymphoid lineage (e.g. leukemia, acutelymphocytic leukemia, mantle cell lymphoma, chronic lymphocyticleukaemia, B-cell lymphoma, (such as diffuse large B cell lymphoma),T-cell lymphoma, multiple myeloma, Hodgkin's lymphoma, non-Hodgkin'slymphoma, hairy cell lymphoma, and Burkett's lymphoma; hematopoietictumours of myeloid lineage, for example acute and chronic myelogenousleukemias, myelodysplastic syndrome, and promyelocytic leukemia. Othercancers include thyroid follicular cancer; a tumour of mesenchymalorigin, for example fibrosarcoma or habdomyosarcoma; a tumour of thecentral or peripheral nervous system, for example astrocytoma,neuroblastoma, glioma or schwannoma; melanoma; seminoma;teratocarcinoma; osteosarcoma; xeroderma pigmentosum; retinoblastoma;keratoctanthoma; thyroid follicular cancer; and Kaposi's sarcoma.

One group of cancers includes human breast cancers (e.g. primary breasttumours, node-negative breast cancer, invasive duct adenocarcinomas ofthe breast, non-endometrioid breast cancers); and endometrial cancers.Another sub-set of cancers wherein compounds having CDK4/6 inhibitoryactivity may be of particular therapeutic benefit comprises glioblastomamultiforme, T cell ALL, sarcomas, familial melanoma and melanoma.

CDK4/6 inhibitors could also be useful in the treatment of viralinfections, for example herpes virus, pox virus, Epstein-Barr virus,Sindbis virus, adenovirus, HIV, HPV, HCV and HCMV; prevention of AIDSdevelopment in HIV-infected individuals; chronic inflammatory diseases,for example systemic lupus erythematosus, autoimmune mediatedglomerulonephritis, rheumatoid arthritis, psoriasis, inflammatory boweldisease, and autoimmune diabetes mellitus; cardiovascular diseases forexample cardiac hypertrophy, restenosis, atherosclerosis;neurodegenerative disorders, for example Alzheimer's disease,AIDS-related dementia, Parkinson's disease, amyotropic lateralsclerosis, retinitis pigmentosa, spinal muscular atropy and cerebellardegeneration; glomerulonephritis; myelodysplastic syndromes, ischemicinjury associated myocardial infarctions, stroke and reperfusion injury,arrhythmia, atherosclerosis, toxin-induced or alcohol related liverdiseases, haematological diseases, for example, chronic anemia andaplastic anemia; degenerative diseases of the musculoskeletal system,for example, osteoporosis and arthritis, aspirin-senstiverhinosinusitis, cystic fibrosis, multiple sclerosis, kidney diseases,ophthalmic diseases including age related macular degeneration, uveitis,and cancer pain.

The methods of treatment of the invention comprise administering atherapeutically effective amount of a compound according to formula (I),or a pharmaceutically acceptable salt thereof, to a subject in needthereof. Individual embodiments of the invention include methods oftreating any one of the above mentioned disorders or diseases byadministering an effective amount of a compound according to formula(I), or a pharmaceutically acceptable salt thereof, to a subject in needthereof.

The term “a therapeutically effective amount” of a compound of thepresent invention refers to an amount of the compound of the presentinvention that will elicit the biological or medical response of asubject, for example, reduction or inhibition of an enzyme or a proteinactivity, or ameliorate symptoms, alleviate conditions, slow or delaydisease progression, or prevent a disease, etc. In one non-limitingembodiment, the term “a therapeutically effective amount” refers to theamount of the compound of the present invention that, when administeredto a subject, is effective to (1) at least partially alleviating,inhibiting, preventing and/or ameliorating a condition, or a disorder ora disease (i) mediated by CDK4/6, or (ii) associated with CDK4/6activity, or (iii) characterized by activity (normal or abnormal) ofCDK4/6; or (2) reducing or inhibiting the activity of CDK4/6; or (3)reducing or inhibiting the expression of CDK4/6. In another non-limitingembodiment, the term “a therapeutically effective amount” refers to theamount of the compound of the present invention that, when administeredto a cell, or a tissue, or a non-cellular biological material, or amedium, is effective to at least partially reducing or inhibiting theactivity of CDK4/6; or at least partially reducing or inhibiting theexpression of CDK4/6. The meaning of the term “a therapeuticallyeffective amount” as illustrated in the above embodiment for CDK4/6 alsoapplies by the same means to any other relevantproteins/peptides/enzymes.

As used herein, the term “subject” refers to an animal. Typically theanimal is a mammal. A subject also refers to for example, primates(e.g., humans, male or female), cows, sheep, goats, horses, dogs, cats,rabbits, rats, mice, fish, birds and the like. In certain embodiments,the subject is a primate. In yet other embodiments, the subject is ahuman.

As used herein, the term “treat”, “treating” or “treatment” of anydisease or disorder refers in one embodiment, to ameliorating thedisease or disorder (i.e., slowing or arresting or reducing thedevelopment of the disease or at least one of the clinical symptomsthereof). In another embodiment “treat”, “treating” or “treatment”refers to alleviating or ameliorating at least one physical parameterincluding those which may not be discernible by the patient. In yetanother embodiment, “treat”, “treating” or “treatment” refers tomodulating the disease or disorder, either physically, (e.g.,stabilization of a discernible symptom), physiologically, (e.g.,stabilization of a physical parameter), or both. In yet anotherembodiment, “treat”, “treating” or “treatment” refers to preventing ordelaying the onset or development or progression of the disease ordisorder.

As used herein, a subject is “in need of” a treatment if such subjectwould benefit biologically, medically or in quality of life from suchtreatment.

The pharmaceutical composition or combination of the present inventioncan be in unit dosage of about 1-1000 mg of active ingredient(s) for asubject of about 50-70 kg, or about 1-500 mg or about 1-250 mg or about1-150 mg or about 0.5-100 mg, or about 1-50 mg of active ingredients.The therapeutically effective dosage of a compound, the pharmaceuticalcomposition, or the combinations thereof, is dependent on the species ofthe subject, the body weight, age and individual condition, the disorderor disease or the severity thereof being treated. A physician, clinicianor veterinarian of ordinary skill can readily determine the effectiveamount of each of the active ingredients necessary to prevent, treat orinhibit the progress of the disorder or disease.

The above-cited dosage properties are demonstrable in vitro and in vivotests using advantageously mammals, e.g., mice, rats, dogs, monkeys orisolated organs, tissues and preparations thereof. The compounds of thepresent invention can be applied in vitro in the form of solutions,e.g., aqueous solutions, and in vivo either enterally, parenterally,advantageously intravenously, e.g., as a suspension or in aqueoussolution. The dosage in vitro may range between about 10⁻³ molar and10⁻⁹ molar concentrations. A therapeutically effective amount in vivomay range depending on the route of administration, between about0.1-500 mg/kg, or between about 1-100 mg/kg.

One embodiment of the present invention includes a method of modulatingCDK4/6 activity in a subject comprising administering to the subject atherapeutically effective amount of a compound according to formula (I)or a pharmaceutically acceptable salt thereof.

Another embodiment of the present invention is a method for thetreatment of a disorder or a disease mediated by CDK4/6 in a subject inneed thereof, comprising administering to the subject a therapeuticallyeffective amount of the compound of formula (I), or a pharmaceuticallyacceptable salt thereof.

Another embodiment of the present invention is a method of treating adisorder or a disease in mediated by CDK4/6, in a subject in need oftreatment thereof comprising administration of a therapeuticallyeffective amount of a compound according to formula (I), or apharmaceutically acceptable salt thereof, wherein the disorder or thedisease is selected from the group consisting of carcinomas with geneticaberrations that activate the CDK4/6 kinase activity. These include, butare not limited to, cancers with D-cyclin translocations such as mantlecell lymphoma and multiple myeloma, D-cyclin amplifications such asbreast cancer and squamous cell esophageal cancer, CDK4 amplificationssuch as liposarcoma, CDK6 amplifications or overexpressions such asT-cell lymphoma and p16 inactivation such as melanoma, non small celllung cancer and pancreatic cancer.

Another embodiment of the present invention is the use of a compound offormula (I), or a pharmaceutically acceptable salt thereof, for thetreatment of a disorder or disease mediated by CDK4.

Another embodiment of the present invention is use of a compound offormula (I), or a pharmaceutically acceptable salt thereof, for thetreatment of a disorder or a disease in mediated by CDK4, in a subjectwherein the disorder or the disease is selected from the groupconsisting of carcinomas with genetic aberrations that activate theCDK4/6 kinase activity. These include, but are not limited to, cancerswith D-cyclin translocations such as mantle cell lymphoma and multiplemyeloma, D-cyclin amplifications such as breast caner and squamous cellesophageal cancer, CDK4 amplifications such as liposarcoma, CDK6amplifications or overexpressions such as T-cell lymphoma and p16inactivation such as melanoma, non-small cell lung cancer and pancreaticcancer.

Another embodiment of the present invention is a compound according toformula (I), or a pharmaceutically acceptable salt thereof, for use as amedicament.

Another embodiment of the present invention is the use of a compound offormula (I), or a pharmaceutically acceptable salt thereof, in themanufacture of a medicament for the treatment of a disorder or diseasemediated by CDK4/6 wherein the disorder or the disease is selected fromthe group consisting of carcinomas with genetic aberrations thatactivate the CDK4/6 kinase activity. These include, but are not limitedto, cancers with D-cyclin translocations such as mantle cell lymphomaand multiple myeloma, D-cyclin amplifications such as breast caner andsquamous cell esophageal cancer, CDK4 amplifications such asliposarcoma, CDK6 amplifications or overexpressions such as T-celllymphoma and p16 inactivation such as melanoma, non-small cell lungcancer and pancreatic cancer.

Combinations

The compounds of the present invention may be administered eithersimultaneously with, or before or after, one or more other therapeuticagents. The compounds of the present invention may be administeredseparately, by the same or different route of administration, ortogether in the same pharmaceutical composition as the other agents.

In one embodiment, the invention provides a product comprising acompound of formula (I), or a pharmaceutically acceptable salt thereof,and at least one other therapeutic agent as a combined preparation forsimultaneous, separate or sequential use in therapy. In one embodiment,the therapy is the treatment of a disease or condition mediated byCDK4/6 inhibition. Products provided as a combined preparation include acomposition comprising the compound of the present invention and theother therapeutic agent(s) together in the same pharmaceuticalcomposition, or the compound of the present invention and the othertherapeutic agent(s) in separate form, e.g. in the form of a kit.

In one embodiment, the invention provides a pharmaceutical compositioncomprising a compound of formula (I) or a pharmaceutically acceptablesalt thereof, and another therapeutic agent(s). Optionally, thepharmaceutical composition may comprise a pharmaceutically acceptableexcipient, as described above.

In one embodiment, the invention provides a kit comprising two or moreseparate pharmaceutical compositions, at least one of which contains acompound of formula (I) or a pharmaceutically acceptable salt thereof.In one embodiment, the kit comprises means for separately retaining saidcompositions, such as a container, divided bottle, or divided foilpacket. An example of such a kit is a blister pack, as typically usedfor the packaging of tablets, capsules and the like.

The kit of the invention may be used for administering different dosageforms, for example, oral and parenteral, for administering the separatecompositions at different dosage intervals, or for titrating theseparate compositions against one another. To assist compliance, the kitof the invention typically comprises directions for administration.

In the combination therapies of the invention, the compound of theinvention and the other therapeutic agent may be manufactured and/orformulated by the same or different manufacturers. Moreover, thecompound of the invention and the other therapeutic may be broughttogether into a combination therapy: (i) prior to release of thecombination product to physicians (e.g. in the case of a kit comprisingthe compound of the invention and the other therapeutic agent); (ii) bythe physician themselves (or under the guidance of the physician)shortly before administration; (iii) in the patient themselves, e.g.during sequential administration of the compound of the invention andthe other therapeutic agent.

Accordingly, the invention provides the use of a compound of formula(I), or a pharmaceutically acceptable salt thereof, for treating adisease or condition mediated by inhibition of CDK4/6, wherein themedicament is prepared for administration with another therapeuticagent. The invention also provides the use of another therapeutic agentfor treating a disease or condition mediated by inhibition of CDK4/6,wherein the medicament is administered with a compound of the presentinvention.

The invention also provides a compound of formula (I), or apharmaceutically acceptable salt thereof, for use in a method oftreating a disease or condition mediated by CDK4/6 inhibition, whereinthe compound of formula (I) is prepared for administration with anothertherapeutic agent. The invention also provides another therapeutic agentfor use in a method of treating a disease or condition mediated byCDK4/6 inhibition, wherein the other therapeutic agent is prepared foradministration with a compound of formula (I) or a pharmaceuticallyacceptable salt thereof. The invention also provides a compound offormula (I), or a pharmaceutically acceptable salt thereof, for use in amethod of treating a disease or condition mediated by CDK4/6 inhibition,wherein the compound of formula (I), or a pharmaceutically acceptablesalt thereof, is administered with another therapeutic agent. Theinvention also provides another therapeutic agent for use in a method oftreating a disease or condition mediated by CDK4/6 inhibition, whereinthe other therapeutic agent is administered with a compound of formula(I).

The invention also provides the use of a compound of formula (I), or apharmaceutically acceptable salt thereof, for treating a disease orcondition mediated by CDK4/6, wherein the patient has previously (e.g.within 24 hours) been treated with another therapeutic agent. Theinvention also provides the use of another therapeutic agent fortreating a disease or condition mediated by CDK4/6, wherein the patienthas previously (e.g. within 24 hours) been treated with a compound offormula (I) or a pharmaceutically acceptable salt thereof.

In one embodiment, the other therapeutic agent is selected from ananti-inflammatory, antiproliferative, chemotherapeutic agent,immunosuppressant, anti-cancer, cytotoxic agent or kinase inhibitorother than a compound of the present invention, or salt thereof. Furtherexamples of agents that may be administered in combination with thecompounds of the invention include, but are not limited to, a PTKinhibitor, cyclosporin A, CTLA4-Ig, antibodies selected fromanti-ICAM-3, anti-IL-2 receptor, anti-CD45RB, anti-CD2, anti-CD3,anti-CD4, anti-CD80, anti-CD86, and monoclonal antibody OKT3, agentsblocking the interaction between CD40 and gp39, fusion proteinsconstructed from CD40 and gp39, inhibitors of NF-kappa B function,non-steroidal antiinflammatory drugs, steroids, gold compounds,antiproliferative agents, FK506, mycophenolate mofetil, cytotoxic drugs,TNF-α inhibitors, anti-TNF antibodies or soluble TNF receptor,rapamycin, mTor inhibitors, leflunimide, cyclooxygenase-2 inhibitors,paclitaxel, cisplatin, carboplatin, doxorubicin, caminomycin,daunorubicin, aminopterin, methotrexate, methopterin, mitomycin C,ecteinascidin 743, porfiromycin, 5-fluorouracil, 6-mercaptopurine,gemcitabine, cytosine arabinoside, podophyllotoxin, etoposide, etoposidephosphate, teniposide, melphalan, vinblastine, vincristine, leurosidine,epothilone, vindesine, leurosine, B-Raf inhibitor, MEK inhibitor, PI3Kinhibitor, HSP90 inhibitor, CDK1 inhibitor, CDK2 inhibitor, CDK5inhibitor, CDK7 inhibitor, CDKB inhibitor, CDK9 inhibitor, EGFRinhibitor, FGFR inhibitor, PDGFR inhibitor, Her2/neu inhibitor, FLT3inhibitor, Antagonists of androgen, glucocorticoid and prosteronereceptors, SMO inhibitor, WNT inhibitor, Bcl inhibitor, IAP inhibitor,Mcl inhibitor, MDM2 inhibitor, p52 inhibitor, proteosome inhibitors(Velcade), or derivatives thereof.

Specific individual combinations which may provide particular treatmentbenefits include co-treatment of mantle cell lymphoma or pancreaticcancer patients with mTOR inhibitors, such as Everolimus.

A compound of the present invention may also be used in combination withother agents, e.g., an additional protein kinase inhibitor that is or isnot a compound of the invention, for treatment of a proteinkinase-associated disorder in a subject. By the term “combination” ismeant either a fixed combination in one dosage unit form, or a kit ofparts for the combined administration where a compound of the presentinvention and a combination partner may be administered independently atthe same time or separately within time intervals that especially allowthat the combination partners show a coope-rative, e.g., synergistic,effect, or any combination thereof.

The compounds of the invention may be administered, simultaneously orsequentially, with an antiinflammatory, antiproliferative,chemotherapeutic agent, immunosuppressant, anti-cancer, cytotoxic agentor kinase inhibitor other than a compound of the Formula I orpharmaceutically acceptable salt thereof. Further examples of agentsthat may be administered in combination with the compounds of theinvention include, but are not limited to, a PTK inhibitor, cyclosporinA, CTLA4-Ig, antibodies selected from anti-ICAM-3, anti-IL-2 receptor,anti-CD45RB, anti-CD2, anti-CD3, anti-CD4, anti-CD80, anti-CD86, andmonoclonal antibody OKT3, agents blocking the interaction between CD40and gp39, fusion proteins constructed from CD40 and gp39, inhibitors ofNF-kappa B function, non-steroidal antiinflammatory drugs, steroids,gold compounds, antiproliferative agents, FK506, mycophenolate mofetil,cytotoxic drugs, TNF-α inhibitors, anti-TNF antibodies or soluble TNFreceptor, rapamycin, leflunimide, cyclooxygenase-2 inhibitors,paclitaxel, cisplatin, carboplatin, doxorubicin, caminomycin,daunorubicin, aminopterin, methotrexate, methopterin, mitomycin C,ecteinascidin 743, porfiromycin, 5-fluorouracil, 6-mercaptopurine,gemcitabine, cytosine arabinoside, podophyllotoxin, etoposide, etoposidephosphate, teniposide, melphalan, vinblastine, vincristine, leurosidine,epothilone, vindesine, leurosine, or derivatives thereof.

A compound of the invention and any additional agent may be formulatedin separate dosage forms. Alternatively, to decrease the number ofdosage forms administered to a patient, the compound of the inventionand any additional agent may be formulated together in any combination.For example, the compound of the invention inhibitor may be formulatedin one dosage form and the additional agent may be formulated togetherin another dosage form. Any separate dosage forms may be administered atthe same time or different times.

Alternatively, a composition of this invention comprises an additionalagent as described herein. Each component may be present in individualcompositions, combination compositions, or in a single composition.

General Synthetic Procedures and Intermediates

General N—C Coupling Procedure 1

To an appropriate reaction vessel was combined compounds of structure 1(1 equivalent) and compounds of general structure 2 (1 equivalent) in anappropriate solvent (such as but not limited to dioxane). To thisresultant solution was added palladium (II) acetate (0.1 equivalent),ligand such as BINAP, XPhos or XantPhos (0.15 equivalent), and cesiumcarbonate (1.5 equivalents). Nitrogen was then gently bubbled throughthe reaction mixture (approximately 5 to 10 minutes). The resultantreaction mixture was then heated using either an oil bath or a microwaveto approximately 100 to 130° C. for an appropriate amount of timewhereby either TLC or HPLC MS analysis indicated that the reaction wascomplete. The reaction was removed from the heat source and allowed tocool. The mixture was then worked up by the addition of an appropriatesolvent such as dichloromethane or ethyl acetate. The insolubles wereremoved by filtration and the organic filtrate extracted with water. Theaqueous phase was back extracted. The organic phases were combined,dried over sodium or magnesium sulfate, filtered and concentrated to aresidue. The crude residue was purified by silica gel chromatographyusing an appropriate mobile phase which yielded the desired intermediateor a compound of Formula (I).

Nitro Group Reduction Procedure 1

An appropriate reaction vessel was charged with a compound of structure3. An appropriate solvent such as methanol, ethyl acetate,tetrahydrofuran or mixtures of these solvents were used to dissolve acompound of structure 3. To this resultant mixture and under a stream ofnitrogen was added a catalyst such as palladium on carbon or palladiumhydroxide (5 to 20% metal content on carbon or a suitable support) in 5to 10 mole percent to structure 3. The resultant mixture was then purgedand stirred under an atmosphere of hydrogen gas. After all the startingmaterial was converted to product as determined by TLC or LCMS, thereaction vessel was removed from the hydrogen source and purged withnitrogen to remove residual hydrogen gas. The reaction mixture wasfiltered through a pad of celite under a stream of nitrogen and washedwith an additional amount of solvent such as dichloromethane ormethanol. The filtrates were combined and concentrated to a residue. Theresidue was dried under vacuum to a constant weight. The resultantmaterial was either used directly in the next reaction or purified byeither re-crystallization or silica gel chromatography and then used inthe next reaction.

Procedures for Preparation of Amides of Formula 1

The following general procedures were used to couple carboxylic acids ofStructure 5 with amines to form the corresponding amides of Structure 6.

General Amide Formation Method 1

To a solution of carboxylic acid (1.01 mmol) in DMF (5 mL) was addedO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(HBTU, 580 mg, 1.53 mmol, 1.5 equiv) and N,N-diisopropylethylamine (0.55mL, 3.0 equiv) and the resulting mixture was stirred at room temperaturefor about 5 minutes. To the resultant mixture was added the Amine (1.18mmol. 1.1 eq). The resulting mixture was stirred at room temperature foran appropriate time as determined by TLC or LCMS for completion and wasthen diluted with ethyl acetate and washed successively with 0.5M HCl,water, dried over Na₂SO₄, filtered and concentrated. The desiredmaterial was either used immediately in next step without furtherpurification or purified by silica gel chromatography using anappropriate mobile phase and then used directly in the next reaction.

General Amide Formation Method 2

To a solution of carboxylic acid (in a salt form with 5 eq. of LiCl) (1mmole, 1 equivalent) in DMF (5 mL) was addedO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(HBTU, 580 mg, 1.53 mmol, 1.5 equiv) and N,N-diisopropylethylamine (0.55mL, 3.0 equiv) and the resulting mixture was stirred at room temperaturefor about 5 minutes. To the resultant mixture was added the Amine (1.18mmol. 1.1 eq). The mixture was stirred at room temperature for anappropriate time for reaction completion as determined by TLC or LCMSand was then diluted with ethyl acetate and washed successively with0.5M HCl, water, dried over Na₂SO₄, filtered and concentrated. Thedesired material was either used immediately in next step withoutfurther purification or purified by silica gel chromatography using anappropriate mobile phase and then used directly in the next reaction.

General Amide Formation Method 3

To a solution of carboxylic acid (1 eq, which contained 5 eq of LiCl) in1 ml of DMA or DMF, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (TBTU, 1 eq.) was added and the resulting solution wasstirred for about 10 min. An additional 3 ml of dichloromethane was thenadded (˜0.03M final concentration), Amine (1 eq.) and DIPEA (4 eq.) werethen added and stirred at RT until TLC and/or LCMS showed reaction wascompleted. The reaction mixture was diluted with dichloromethane, washedwith water and then brine. The combined aqueous layers were backextracted with dichloromethane. The combined organic layers were driedover sodium sulfate or magnesium sulfate, then filtered, thenconcentrated and finally purified by silica gel column chromatographyusing an appropriate mobile phase and then used directly in the nextreaction.

General Amide Formation Method 4

To a suspension/solution of a mixture of carboxylic acid (with the 5equiv LiCl) (1 eq) in DMA/DCM (1:4, 0.07M) was addedO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU, 1.5 eq, general procedure B1) orO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(HBTU, 1.5 equiv, general procedure B2) and the resulting mixture wasstirred at room temperature for 5 min. The reaction mixture was treatedwith a solution of the Amine (1 equiv) in DMA/DCM (1:4, 0.07M) or asuspension of HCl salt of Amine (1.0 equiv) and sodium bicarbonate (1.5quiv) in in DMA/DCM (1:4, 0.07M). The resulting mixture was treated withN,N-diisopropylethylamine (4.0 eq) and stirred at room temperature for 1h. The reaction mixture was diluted in ethyl acetate, washed with water,dried over Na₂SO₄, filtered and concentrated. The resultant residue waspurified by silica gel column chromatography using an appropriate mobilephase and then used in the next reaction.

General Procedures for the Removal of Protecting Groups of Intermediates

Intermediates which contained protecting groups necessary for thesynthesis of final compounds of Formula (I), these protecting groupswere removed by standard procedures as described in “Protective Groupsin Organic Synthesis, 3^(rd) Edition, by Green and Wutts.

Deprotection Method 1: BOC Removal Using HCl

To a stirring solution of the BOC protected amine of a compound offormula 1, (1. mmol) in dichloromethane (4 m L) or other appropriatesolvent was added a solution of 4M HCl in dioxane (2.54 mL, 10.2 mmol,10 eq) at room temperature. The reaction was stirred at room temperatureuntil all starting material was consumed as determined by LCMS or TLC.The reaction mixture was then filtered and washed with a solvent such asdichloromethane, ethyl acetate or diethyl ether. The residue wascollected and taken up in water, basified with 1M NaOH and extractedwith dichloromethane or a 20% isopropyl aclohol-dichloromethane mixture.The combined organic layers were dried over Na2SO4, filtered, andconcentrated under reduced pressure to a residue. The crude residue waspurified by silica gel chromatography using an appropriate mobile phaseand then used directly in the next reaction.

Deprotection Method 2: BOC Removal Using Trifluoroacetic Acid

To a cold 0° C. stirring solution of the BOC protected amine of acompound of Formula 1, (1. mmol) in dichloromethane (4 mL) or otherappropriate solvent was added 4 ml of anhydrous trifluoroacetic acid.The reaction was stirred at 0° C. and allowed to warm to roomtemperature and stir until all starting material was consumed asdetermined by LCMS or TLC. The reaction mixture was then concentratedunder vacuum to a thick residue. The residue was extracted with amixture of dichloromethane and saturated sodium bicarbonate. The aqueouswas back extracted with dichloromethane. For very polar amines, a 20%isopropyl alcohol-dichloromethane mixture was used for the organicextracting solvent. The organic fractions were combined and dried overNa₂SO₄, filtered, and concentrated under reduced pressure to a residue.The combined organic layers were dried over sodium or magnesium sulfate,filtered, and concentrated under reduced pressure to a residue. Thecrude residue was purified by silica gel chromatography using anappropriate mobile phase and then used directly in the next reaction.

Deprotection Method 3: BOC Removal Using Trifluoroacetic Acid

A solution of the BOC protected amine of a compound of formula 1 inCH₂Cl₂ (0.1M) was treated with an equal volume of trifluoroacetic acidat room temperature and stirred at room temperature for 1.0 h. Thereaction mixture was concentrated in vacuo and treated with 7 N NH₃ inMeOH portionwise until the mixture was neutral. The resultant mixturewas concentrated to a thick residue. The resultant residue was thenpurified by preparative HPLC or silica gel chromatography using 7 N NH₃in MeOH/CH₂Cl₂ and then used directly in the next reaction.

General Reductive Amination Procedure

A compound of Formula (I) (1 equivalent) containing either a primary orsecondary amine and with an excess (3 to 8 equivalents) of either analdehyde (for example, formaldehyde, 37% solution in water) or ketone(for example, acetone) were combined into a suitable solvent such astetrahydrofuran and allowed to stir at RT for 1 hr with magnesiumsulfate (1 equivalent). Sodium triacetoxyborohydride (2 equivalents) wasthen added in a single portion and the reaction was allowed to stiruntil all starting material was consumed as determined by TLC or LCMS.The reaction was then stopped and taken up into ethyl acetate,neutralized with saturated Na₂CO₃ solution, and washed with brine. Theaqueous layers were back extracted with ethyl acetate. The organiclayers were combined and dried over Na₂SO₄. For very polar amines, a 20%isopropanol-chloroform solution was used as the extracting solvent. Thevolatiles were removed and the resulting residue was purified by silicagel chromatography using an appropriate mobile phase which gave thedesired final product.

Procedures for the preparation of 2-chloro-7R¹—N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamides intermediates

2 chloro-7 R²—N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

Intermediate 1:

Preparation of2-chloro-7-cycloheptyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

Step 1

To a solution of 5-bromo-2,4-dichloropyrimidine (13.41 g, 58.8 mmol) inEtOAc (100 mL) was added DIPEA (13 mL, 1.3 equiv) followed bycycloheptanamine (8.6 mL, 1.1 equiv) and the resulting mixture wasstirred at room temperature for 5 days. The reaction mixture was dilutedwith EtOAc (350 mL), washed with water (100 mL), brine (2×100 mL), driedover Na2SO4, filtered and concentrated. The crude product (18.1 g) wasused for the next reaction without purification. 1H NMR (400 MHz, CD3OD)δ 8.10 (s, 1H), 4.17 (septet, J=4.6 Hz, 1H), 1.94 (m, 2H), 1.77-1.51 (m,10 Hz); MS m/z 305.3 (M+H)⁺

Step 2

Preparation of3-(2-chloro-4-(cycloheptylamino)pyrimidin-5-yl)prop-2-yn-1-ol

To a yellow solution of 5-bromo-2-chloro-N-cycloheptylpyrimidin-4-amine(18.1 g, 55.5 mmol) in THF (200 mL) were added propargyl alcohol (4.5mL, 1.4 equiv) and a solution of tetrabutylammonium fluoride in THF (1M, 130 mL, 2.3 equiv) and the resulting brown mixture was treated with astream of nitrogen for 15 min (bubble in the solution). The mixture wasthen treated with bis(triphenylphosphine)palladium(II) chloride (2.09 g,0.054 equiv) and heated to reflux for 5 h. After cooling, the reactionmixture was filtered through a pad of celite (rinsed with EtOAc ˜350mL). The filtrate was concentrated to remove THF, further diluted withEtOAc (total volume 250 mL), washed with sat. NaHCO3 (2×150 mL) andwater (150 mL), dried over Na2SO4, filtered and concentrated. Titrationof the residue in acetone and CH2Cl2 provided3-(2-chloro-4-(cycloheptylamino)pyrimidin-5-yl)prop-2-yn-1-ol (8.65 g)in 56% yield. 1H NMR (400 MHz, CD3OD) δ 7.98 (s, 1H), 4.45 (s, 2H), 4.19(septet, J=4.5 Hz, 1H), 1.95 (m, 2H), 1.77-1.52 (m, 10 Hz); MS m/z 280.4(M+

Step 3

Preparation of(2-chloro-7-cycloheptyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)methanol

To a suspension of3-(2-chloro-4-(cycloheptylamino)pyrimidin-5-yl)prop-2-yn-1-ol (8.64 g,30.9 mmol) in THF (200 mL) was added a solution of TBAF in THF (1 M, 66mL, 2.1 equiv) and the resulting mixture was heated at 63° C. for 5 h.The reaction mixture was concentrated to remove THF, diluted with EtOAc(350 mL), washed with water (140 mL) and brine (140 mL), dried overNa2SO4, filtered and concentrated. Trituration of the residue usingiPrOH, CH2Cl2, and MeCN followed by column chromatography of the motherliquor (EtOAc/heptane 20 to 100%) provided(2-chloro-7-cycloheptyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)methanol (6.24g) in 72% yield. 1H NMR (400 MHz, CDCl3) δ 8.69 (s, 1H), 6.45 (s, 1H),4.83 (s, 2H), 4.61 (m, 1H), 2.54 (m, 2H), 1.98-1.86 (m, 4H), 1.73-1.55(m, 6H); MS m/z 280.4 (M+H)⁺

Step 4

Preparation of2-chloro-7-cycloheptyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

To a solution of(2-chloro-7-cycloheptyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)methanol (6.24g, 22.3 mmol) in DMF (100 mL) were added a solution of dimethylamine inTHF (2 M, 46 mL, 4.1 equiv) and sodium cyanide (1.04 g, 0.95 equiv) andthe resulting mixture was stirred at room temperature for 4 min. Thereaction mixture was treated with manganese dioxide (100.4 g, 45 equiv)in four portions over 1 h and stirred for additional 1 h. The reactionmixture was filtered through a pad of Celite (rinsed with EtOAc 600 mL).The filtrate was washed with water (200 mL). The aqueous phase wasextracted with EtOAc (2×150 mL). Combined organics were washed with 4%aqueous solution of NaCl (2×250 mL), dried over Na2SO4, filtered andconcentrated in vacuo. Trituration of the residue in MeCN followed bycolumn chromatography of the mother liquor (EtOAc/Heptane 30 to 100%)provided2-chloro-7-cycloheptyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide(6.07 g) in 85% yield. 1H NMR (400 MHz, CDCl3) δ 8.81 (s, 1H), 6.52 (s,1H), 4.63 (tt, J=11, 4.0 Hz, 1H), 3.20 (s, 3H), 3.11 (s, 3H), 2.52 (m,2H), 1.99 (m, 2H), 1.88 (m, 2H), 1.70 (m, 4H), 1.58 (m, 2H) MS m/z 321.5(M+H)⁺

Intermediate 2:

2-chloro-7-cyclohexyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamidewas prepared in a similar manner to intermediate 1

Step 1

(5-Bromo-2-chloro-pyrimidin-4-yl)-cyclohexyl-amine (23.2 g, 78% yield):1H NMR (400 MHz, DMSO-d₆) δ ppm 1.01-1.17 (m, 1H) 1.20-1.31 (m, 3H)1.35-1.50 (m, 2H) 1.60 (d, J=12.5 Hz, 1H) 1.65-1.83 (m, 4H) 3.89 (ddd,J=7.8, 3.8, 3.5 Hz, 1H) 7.26 (d, J=8.0 Hz, 1H) 8.22 (s, 1H); MS m/z290.4 (M)⁺.

Step 2

3-(2-Chloro-4-cyclohexylaminopyrimidin-5-yl)-prop-2-yn-1-ol (9.1 g, 43%yield): 1H NMR (400 MHz, DMSO-d₆) δ ppm 1.14 (t, J=12.9 Hz, 1H)1.23-1.49 (m, 4H) 1.62 (d, J=13.1 Hz, 1H) 1.67-1.88 (m, 4H) 3.83-3.99(m, 1H) 4.35 (d, J=6.1 Hz, 2H) 5.37 (t, J=5.8 Hz, 1H) 7.00 (d, J=8.1 Hz,1H); MS m/z 266.3 (M+H)⁺.

Step 3

(2-Chloro-7-cyclohexyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-methanol (7.3 g,81% yield): 1H NMR (400 MHz, DMSO-d₆) δ ppm 1.28 (t, J=12.6 Hz, 1H)1.33-1.48 (m, 2H) 1.70 (d, J=12.1 Hz, 1H) 1.78-1.93 (m, 4H) 2.34-2.48(m, 2H) 4.24-4.42 (m, 1H) 4.67 (d, J=5.1 Hz, 2H) 5.50 (t, J=5.6 Hz, 1H)6.55 (s, 1H) 8.82 (s, 1H); MS m/z 266.5 (M+H)⁺.

Step 4

2-Chloro-7-cyclohexyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic aciddimethylamide (0.85 g, 64% yield): 1H NMR (400 MHz, DMSO-d₆) δ ppm 1.22(br. s., 1H) 1.36 (d, J=13.6 Hz, 2H) 1.66 (br. s., 1H) 1.85 (d, J=10.6Hz, 4H) 2.30 (dd, J=12.4, 3.3 Hz, 2H) 3.04 (d, J=17.2 Hz, 6H) 4.34 (br.s., 1H) 6.80 (s, 1H) 8.97 (s, 1H); MS m/z 307.3 (M+H)⁺.

Intermediate 3:

Following the procedure for the preparation of intermediate one,2-chloro-7-cyclopentyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamidewas prepared in a similar manner and is a known literature compound (seeWO 2010/020675)

Intermediate 4:

Following the procedure for the preparation of intermediate one,2-chloro-N,N-dimethyl-7-(tetrahydro-2H-pyran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamidewas prepared in a similar manner.

Step 1

5-bromo-2-chloro-N-(tetrahydro-2H-pyran-3-yl)pyrimidin-4-amine (6.47 g)was prepared in 83% yield. 1H NMR (400 MHz, CD3OD) δ 8.16 (s, 1H), 4.20(septet, J=4.0 Hz, 1H), 3.89 (ddd, J=11, 4.0, 1.5 Hz, 1H), 3.79 (dt,J=11, 4.0 Hz, 1H), 3.53 (m, 1H), 3.40 (dd, J=11, 8.1 Hz, 1H), 2.0 (m,1H), 1.82-1.66 (m, 3H); MS m/z 293.3 (M+H)⁺

Step 2

3-(2-chloro-4-(tetrahydro-2H-pyran-3-ylamino)pyrimidin-5-yl)prop-2-yn-1-01(3.21 g) was prepared in 54% yield. 1H NMR (400 MHz, CD3OD) δ 8.05 (s,1H), 4.45 (s, 1H), 4.21 (septet, J=4.0 Hz, 1H), 3.90 (ddd, J=11, 4.0,1.0 Hz, 1H), 3.80 (dt, J=11, 4.0 Hz, 1H), 3.52 (m, 1H), 3.39 (dd, J=11,8.3 Hz, 1H), 2.01 (m, 1H), 1.81-1.67 (m, 3H); MS m/z 268.4 (M+H)⁺

Step 3

(2-chloro-7-(tetrahydro-2H-pyran-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)methanol(2.39 g) was prepared in 75% yield. 1H NMR (400 MHz, CD3OD) δ 8.72 (s,1H), 6.59 (s, 1H), 4.77 (s, 2H), 4.62 (m, 1H), 4.42 (t, J=11 Hz, 1H),4.00-3.91 (m, 2H), 3.57 (m, 1H), 2.92 (m, 1H), 2.07 (m, 1H), 1.87 (m,2H); MS m/z 268.4 (M+H)⁺

Step 4

2-chloro-N,N-dimethyl-7-(tetrahydro-2H-pyran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide(1.74 g) was prepared in 58% yield. 1H NMR (400 MHz, CD3OD) δ 8.87 (s,1H), 6.81 (s, 1H), 4.53 (tt, J=11, 4.4 Hz, 1H), 4.32 (t, J=11 Hz, 1H),3.95 (m, 2H), 3.52 (m, 1H), 3.17 (s, 3H), 3.15 (s, 3H), 2.77 (qt, J=12,5.3 Hz, 1H), 2.09 (m, 1H), 1.57-1.78 (m, 2H); MS m/z 309.5 (M+H)⁺

Intermediate 5

Following the procedure for the preparation of intermediate one,2-chloro-7-(4-(2-cyanopropan-2-yl)phenyl)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamidewas prepared in a similar manner to intermediate 1.

Step 1:

2-(4-(5-bromo-2-chloropyrimidin-4-ylamino)phenyl)-2-methylpropanenitrile

5-Bromo-2,4-dichloropyrimidine (1.37 gm, 6 mmol),2-(4-aminophenyl)-2-methylpropanenitrile (0.96 gm, 6 mmol) anddiisopropyl ethylamine (1.6 mL, 9 mmol) were combined in 30 mlacetonitrile and stirred for 16 hr at RT. LC/MS at 16 hr indicatedreaction was complete. Organics were washed sequentially with 1M citricacid solution, water, then brine. Organics were dried over sodiumsulfate then decanted and evaporated to yield a crude material which wascarried on as-is in the next step. (1.45 gm, 69%). MS m/z 353.3 (M+H)

Step 2:

2-(4-(2-chloro-5-(3-hydroxyprop-1-ynyl)pyrimidin-4-ylamino)phenyl)-2-methylpropanenitrile

2-(4-(5-bromo-2-chloropyrimidin-4-ylamino)phenyl)-2-methylpropanenitrile(1.4 gm, 3.98 mmol), bis(triphenylphosphine) palladium(II) chloride(0.14 gm, 0.2 mmol), tetrabutyl ammonium fluoride (2.6 gm, 9.95 mmol)and propargyl alcohol (0.357 mL, 5.97 mmol) were combined into 12 mL THFin a screw cap high pressure vessel and heated in a 70° C. oil bath.After 2 hr the reaction appeared complete by LC/MS. Volatiles wereremoved and the residue taken up into EtOAc. Organic layer was filteredto remove insoluble soot. Organic layer was washed with water, brine andthen dried over sodium sulfate. Volatiles were removed and the residuepurified by NPLC (10-75% EtOAc in Heptane, Analogix). (869 mg, 67%). MSm/z 327.4 (M+H)

Step 3:

2-(4-(2-chloro-6-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-2-methylpropanenitrile

2-(4-(2-chloro-5-(3-hydroxyprop-1-ynyl)pyrimidin-4-ylamino)phenyl)-2-methylpropanenitrilewas reacted with a solution of 1M tetrabutylammonium fluoride in THF(5.85 mL, 5.85 mmol) diluted to 10 mL with additional dry THF for 1.5 hrat 60° C. Analytical LC indicates the reaction is complete (minimalshift in retention time). Volatiles were removed and the residue takenup into ethyl acetate. Organics were washed with water, brine then driedover sodium sulfate. Volatiles were removed and the residue purified byNPLC (10-75% ethyl acetate in Heptane, Analogix) to yield the desiredproduct (589 mg, 68%). MS 327.3 m/z (M+H)

Step 4:

2-chloro-7-(4-(2-cyanopropan-2-yl)phenyl)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

2-(4-(2-chloro-6-(hydroxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yOphenyl)-2-methylpropanenitrile(589 mg, 1.8 mmol), manganese dioxide (7.8 gm, 90 mmol) and 2 Mdimethylamine solution in THF (4.51 ml, 9 mmol) were combined in 6 mLdry DMF. Reaction was stirred for 3 hrs whereupon the reaction appearedcomplete by LC/MS. Reaction was poured into brine and extracted intoEtOAc. Combined organics were washed with water followed by brine andthen dried over sodium sulfate. Volatiles were removed and the residuepurified by NPLC (10-100% ethyl acetate in heptane, Analogix) to yieldthe pure desired compound. (345 mg, 52%). MS 367.7 m/z

Intermediate 6

6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinicacid LiCl salt

Step 1

Preparation of Methyl6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinate

To a suspension of2-chloro-7-cyclopentyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide(5.0 g, 17 mmol) in 1,4-dioxane (80 mL) in a sealed tube were addedmethyl 6-aminonicotinate (2.86 g, 1.10 eq), Pd(OAc)₂ (0.096 g, 0.025 eq)and BINAP (0.532 g, 0.050 eq). N2 was bubbled through the resultingmixture for 20 min to degas and treated with Cs₂CO₃ (8.35 g, 1.5 eq).The reaction mixture was heated at 100° C. for 2.2 h. The reactionmixture was cooled to room temperature, treated with 100 mL of heptaneand sonicated. Red precipitate was collected by filtration and suspendedin 200 mL of water. After sonication, the solid was collected byfiltration, rinsed with water (3×50 mL) and dried. The solid wastriturated in THF to obtain tan solid methyl6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinate(6.6 g, 94% yield). The filtrated was concentrated in vacuo and purifiedby column chromatography (Ethyl acetate/Heptane) to give additionalproduct (0.4 g, 6% yield). ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.33 (s,1H), 8.89 (s, 1H), 8.83 (d, J=2.1 Hz, 1H), 8.44 (d, J=8.9 Hz, 1H), 8.22(dd, J=8.9, 2.2 Hz, 1H), 6.67 (s, 1H), 4.77 (m, 1H), 3.86 (s, 3H), 3.06(s, 6H), 2.42 (m, 2H), 2.00 (m, 4H), 1.68 (m, 2H); MS m/z 409.4 (M+H)⁺.

Step 2

Preparation of6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinicacid LiCl salt

To a suspension of methyl6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinate(1.0 g, 2.4 mmol) in 2-propanol (60 mL) were added LiON (0.29 g, 5.0 eq)and water (12 mL) and the resulting mixture was stirred at 60° C. for 1h. the suspension became clear gradually. After cooling to roomtemperature, the reaction mixture was treated with 1 N HCl (12.24 mL, 5eq) and concentrated in vacuo. Light yellow solid (1.40 g, 95% yield) ofa mixture of6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinicacid and LiCl (5 equiv) was used for the next reaction without furtherpurification. ¹H NMR (400 MHz, DMSO-d6) δ ppm 13.30 (br s, 1H), 11.24(br s, 1H), 9.03 (s, 1H), 8.88 (d, J=2.2 Hz, 1H), 8.31 (dd, J=8.7, 2.2Hz, 1H), 8.11 (d, J=8.7 Hz, 1H), 6.81 (s, 1H), 4.79 (m, 1H), 3.06 (s,6H), 2.41 (m, 2H), 2.02 (m, 4H), 1.67 (m, 2H); MS ink 395.4 (M+H)⁺.

Intermediate 7

Preparation of6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinic acid

To a suspension of methyl6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinate(2.0 g, 4.9 mmol) in THF (6 mL) was added 1M LiOH (aq) (6 mL, 1.2 equiv)and the slurry stirred at 45° C. for 12 hours (the slurry became clear).After cooling to room temperature, the THF was evaporated and thereaction mixture was treated with 1 N HCl until pH=1-2. The resultingprecipitate was filtered and the filtrate extracted with 20%Isopropanol/CH₂Cl₂ (3×100 mL), the combined organic layers dried,filtered, and concentrated to a tan solid. The tan solid was trituratedin acetone giving6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinic acid as the desired product as a tan solid (1.56 g, 73% yield)which was used without further purification.

¹H NMR (400 MHz, DMSO-d₆) δ 10.75 (br. s, 1H), 8.95 (s, 1H), 8.84 (d,J=2.5 Hz, 1H), 8.24-8.33 (m, 1H), 8.13-8.24 (m, 1H), 6.74 (s, 1H), 4.79(quin, J=8.8 Hz, 1H), 3.06 (s, 1H), 2.30-2.46 (m, 3H), 1.90-2.09 (m,5H), 1.48-1.76 (m, 3H), 1.04 (d, J=6.1 Hz, 1H); MS m/z 395.5 (M+H)⁺

Intermediate 8

Following the procedure for the preparation of intermediate one,2-chloro-7-(4-(2-cyanopropan-2-yl)phenyl)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamidewas prepared in a similar manner to intermediate 1

6-(7-Cycloheptyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-nicotinicacid

Step 1

To a mixture of2-Chloro-7-cycloheptyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic aciddimethylamide (517 mg, 1.2 mmol, 1.0 eq), 6-Amino-nicotinic acid methylester (221 mg, 1.5 mmol, 1.2 eq), Cs₂CO₃ (591 mg, 1.8 mmol, 1.5 eq) andBINAP (38 mg, 0.06 mmol, 0.05 eq) was bubbled in N₂ via a pipette for 3min. Pd(OAc)₂ (14 mg, 0.06 mmol, 0.05 eq) was added and the flask wassealed and stirred in an oil bath heated to 130° C. for 3 hr. Themixture was filtered through a pad of celite and washed with etOAc. Theorganic layer was washed with water, then brine and the organic layerscombined, dried over Na₂SO₄. The solvent was evaporated and the brownsolid was triturated with acetonitrile, filtered, washed with ACN anddried under high vacuum to yield the title compound as a light pinksolid (236 mg, 0.53 mmol, 44% yield). ¹H NMR (400 MHz, chloroform-d) δppm 8.84-8.90 (m, 1H) 8.69 (s, 1H) 8.61 (d, J=9.09 Hz, 1H) 8.51 (br s,1H) 8.20-8.26 (m, 1H) 6.40 (s, 1H) 4.40-4.53 (m, 1H) 3.87 (s, 3H) 3.10(s, 6H) 2.48-2.64 (m, 2H) 1.90-2.00 (m, 2H) 1.76-1.86 (m, 2H) 1.63-1.72(m, 4H) 1.45-1.56 (m, 2H). MS (m/z, MH+): 437.5

Step 2

Preparation of6-(7-Cycloheptyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-nicotinicacid

To a solution of6-(7-Cycloheptyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-nicotinicacid methyl ester (146 mg, 0.33 mmol, 1.0 eq) in THF (1.5 mL) was addedLiOH (94.7 mg, 4.0 mmol, 12 eq) in 1.5 mL of water. The mixture wasstirred at room temperature for 48 h. The reaction mixture was cooled to0° C. in an ice bath and was acidified with 1 N HCl until pH was about1-2. The solid precipitate was filtered and washed to give the titlecompound as a light pink solid (52 mg, 0.124 mmol, 37%) and used as is;alternatively it can be extracted out with 20% Isopropanol indichloromethane) ¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.99 (br s, 1H) 10.38(br s, 1H) 8.87 (s, 1H) 8.81 (d, J=2.01 Hz, 1H) 8.53 (d, J=9.03 Hz, 1H)8.19 (dd, J=9.03, 2.01 Hz, 1H) 6.67 (s, 1H) 4.44 (br s, 1H) 3.07 (d,J=13.05 Hz, 6H) 2.54-2.60 (m, 2H) 1.87-1.98 (m, 2H) 1.75-1.87 (m, 2H)1.59-1.75 (m, 4H) 1.49 (m, 2H). MS (m/z, MH+): 423.5

Intermediate 9

Following the procedure for the preparation of intermediate 6,6-(7-cycloheptyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinicacid and 5 equiv LiCl was prepared in a similar manner to intermediate6. ¹H NMR (400 MHz, DMSO-d6) δ ppm 9.70 (br s, 1H), 8.81 (s, 1H), 8.71(s, 1H), 8.42 (d, J=8.53 Hz, 1H), 8.10 (dd, J1=8.53, J2=2.01 Hz, 1H),6.63 (s, 1H), 4.41 (m, 1H), 3.07 (d, 6H), 2.70-2.52 (m, 2H), 1.99-1.39(m, 10H)

MS m/z 422.9 (M+H)⁺.

EXAMPLES Example 1

7-Cyclopentyl-2-(5-((1R,5S)-9-hydroxy-3,7-diazabicyclo[3.3.1]nonane-3-carbonyl)pyridin-2-ylamino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

Step 1.

Preparation of Methyl6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinate

Following general N—C coupling procedure 1,2-chloro-7-cyclopentyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide(5.0 g, 17 mmol) was combined with methyl 6-aminonicotinate (2.86 g,1.10 eq) which gave methyl6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinate(6.6 g) in 94% yield. ¹H NMR (400 MHz, DMSO-d6) δ ppm 10.33 (s, 1H),8.89 (s, 1H), 8.83 (d, J=2.1 Hz, 1H), 8.44 (d, J=8.9 Hz, 1H), 8.22 (dd,J=8.9, 2.2 Hz, 1H), 6.67 (s, 1H), 4.77 (m, 1H), 3.86 (s, 3H), 3.06 (s,6H), 2.42 (m, 2H), 2.00 (m, 4H), 1.68 (m, 2H); MS m/z 409.4 (M+H)⁺.

Step 2.

Preparation of6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinicacid and 5 equiv LiCl

To a suspension of methyl6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinate(1.0 g, 2.4 mmol) in 2-propanol (60 mL) were added LiOH (0.29 g, 5.0 eq)and water (12 mL) and the resulting mixture was stirred at 60° C. for 1h. After cooling to room temperature, the reaction mixture was treatedwith 1 N HCl (12.24 mL, 5 eq) and concentrated in vacuo which gave6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinicacid as a light yellow solid (1.40 g) in 95% yield as the LiCl (5 equiv)co-salt and was used for the next reaction without further purification.¹H NMR (400 MHz, DMSO-d6) δ ppm 13.30 (br s, 1H), 11.24 (br s, 1H), 9.03(s, 1H), 8.88 (d, J=2.2 Hz, 1H), 8.31 (dd, J=8.7, 2.2 Hz, 1H), 8.11 (d,J=8.7 Hz, 1H), 6.81 (s, 1H), 4.79 (m, 1H), 3.06 (s, 6H), 2.41 (m, 2H),2.02 (m, 4H), 1.67 (m, 2H); MS m/z 395.4 (M+H)⁺.

Step 3.

Following general amide formation method 1,6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinicacid with 5 equiv LiCl was combined with (1R,5S)-tert-butyl9-hydroxy-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate which gave(1R,5S)-tert-butyl7-(6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinoyl)-9-hydroxy-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate(158 mg) in 77% yield. ¹H NMR (400 MHz, CDCl₃) δ ppm 8.76 (s, 1H), 8.56(d, J=8.59 Hz, 1H), 8.41 (s, 1H), 8.28 (br s, 1H), 7.92 (d, J=7.07 Hz,1H), 6.47 (s, 1H), 4.80 (m, 1H), 4.67-4.29 (m, 2H), 4.14-3.68 (m, 3H),3.48 (m, 1H), 3.24-2.99 (m, 7H), 2.60 (m, 2H), 2.26-1.54 (m, 10H), 1.49(s, 9H); LCMS m/z 619.0 (M+H)⁺.

Step 4.

Preparation of7-Cyclopentyl-2-(5-((1R,5S)-9-hydroxy-3,7-diazabicyclo[3.3.1]nonane-3-carbonyl)pyridin-2-ylamino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

Following deprotection method 2, (1R,5S)-tert-butyl7-(6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinoyl)-9-hydroxy-3,7-diazabicyclo[3.3.1]nonane-3-carboxylatewas converted to7-Cyclopentyl-2-(5-((1R,5S)-9-hydroxy-3,7-diazabicyclo[3.3.1]nonane-3-carbonyl)pyridin-2-ylamino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide(47 mg) in 93% yield. ¹H NMR (400 MHz, CDCl₃) δ ppm 9.04 (s, 1H), 8.85(s, 1H), 8.60 (d, J=8.59 Hz, 1H), 8.50 (s, 1H), 7.83 (dd, J1=8.84 Hz,J2=2.27 Hz, 1H), 6.49 (s, 1H), 4.91-4.33 (m, 2H), 4.16-3.10 (m, 12H),3.10-2.36 (m, 5H), 2.28-1.53 (m, 8H); HRMS m/z 519.2849 (M+H)⁺.

Example 2

7-cycloheptyl-2-(5-((1R,5S)-9-hydroxy-3,7-diazabicyclo[3.3.1]nonane-3-carbonyl)pyridin-2-ylamino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

Step 1.

Preparation of6-(7-cycloheptyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinicacid-5 LiCl

Following step 1 in the preparation of EXAMPLE 1, in an analogousmanner,6-(7-cycloheptyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-nicotinicacid methyl ester (1.34 g) was obtained in 52% yield. ¹H NMR (400 MHz,CDCl3) δ ppm 8.95 (d, J=2.0 Hz, 1H), 8.77 (s, 1H), 8.71 (d, J=8.6 Hz,1H), 8.33 (dd, J=8.8, 2.1 Hz, 1H), 6.50 (s, 1H), 4.55 (m, 1H), 3.97 (s,3H), 3.29 (s, 6H), 2.65 (m, 2H), 2.04 (m, 2H), 1.91 (m, 2H), 1.83-1.70(m, 4H), 1.60 (m, 2H); MS m/z 437.5 (M+H)⁺.

Step 2.

Preparation of6-(7-cycloheptyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinicacid and 5 equiv LiCl

Following step 2 in the preparation of example 1, in an analogousmanner,6-(7-cycloheptyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinicacid-5 equiv LiCl (1.87 g) was obtained in quantitative yield. ¹H NMR(400 MHz, DMSO-d6) δ ppm 9.70 (br s, 1H), 8.81 (s, 1H), 8.71 (s, 1H),8.42 (d, J=8.53 Hz, 1H), 8.10 (dd, J1=8.53, J2=2.01 Hz, 1H), 6.63 (s,1H), 4.41 (m, 1H), 3.07 (d, 6H), 2.70-2.52 (m, 2H), 1.99-1.39 (m, 10H);MS m/z 422.9 (M+H)⁺.

Step 3.

Preparation of7-cycloheptyl-2-(5-((1R,5S)-9-hydroxy-3,7-diazabicyclo[3.3.1]nonane-3-carbonyl)pyridin-2-ylamino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

Following general amide formation method 1,6-(7-cycloheptyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinicacid with 5 equiv LiCl was combined with (1R,5S)-tert-butyl9-hydroxy-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate which gave(1R,5S)-tert-butyl7-(6-(7-cycloheptyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinoyl)-9-hydroxy-3,7-diazabicyclo[3.3.1]nonane-3-carboxylate(170 mg) in 83% yield. ¹H NMR (400 MHz, CDCl₃) δ ppm 8.75 (s, 1H), 8.67(d, J=8.59 Hz, 1H), 8.42 (s, 1H), 8.31 (br s, 1H), 7.92 (d, J=8.08 Hz,1H), 6.46 (s, 1H), 4.74-3.40 (m, 7H), 3.22-2.94 (m, 7H), 2.65 (m, 2H),2.16-1.54 (m, 13H), 1.49 (s, 9H); LCMS m/z 647.1 (M+H)⁺.

Step 4.

Preparation of7-cycloheptyl-2-(5-((1R,5S)-9-hydroxy-3,7-diazabicyclo[3.3.1]nonane-3-carbonyl)pyridin-2-ylamino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

Following deprotection method 2, (1R,5S)-tert-butyl7-(6-(7-cycloheptyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinoyl)-9-hydroxy-3,7-diazabicyclo[3.3.1]nonane-3-carboxylatewas converted to7-cycloheptyl-2-(5-((1R,5S)-9-hydroxy-3,7-diazabicyclo[3.3.1]nonane-3-carbonyl)pyridin-2-ylamino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide(43 mg) in 96% yield. ¹H NMR (400 MHz, CDCl₃) δ ppm 9.34 (s, 1H), 8.88(m, 1H), 8.74 (m, 1H), 8.54 (m, 1H), 7.85 (dd, J1=8.59 Hz, J2=2.02 Hz,1H), 6.48 (s, 1H), 4.80-4.38 (m, 2H), 4.17-3.09 (m, 12H), 3.07-2.52 (m,5H), 2.23-1.50 (m, 12H); HRMS m/z 547.3161 (M+H)⁺.

Example 3

7-Cycloheptyl-2-[5-(2,5-diaza-bicyclo[2.2.1]heptane-2-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Step 1.

Preparation of5-[6-(7-Cycloheptyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylicacid tert-butyl ester

Following general amide formation method 1,6-(7-Cycloheptyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-nicotinicacid (52.5 mg, 0.124 mmol, 1.0 eq) was combined with2,5-Diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (32.0mg, 0.162 mmol, 1.5 eq) which gave5-[6-(7-Cycloheptyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylicacid tert-butyl ester (59 mg, 0.09 mmol, 76% yield). ¹H NMR (400 MHz,chloroform-d) δ ppm 9.12 (br s, 1H) 8.85 (s, 1H) 8.73 (br s, 1H) 8.61(br s, 1H) 7.98 (br s, 1H) 6.48 (s, 1H) 4.47-4.65 (m, 2H) 3.72 (br s,1H) 3.52-3.69 (m, 2H) 3.46 (t, J=8.59 Hz, 1H) 3.18 (s, 6H) 2.58-2.74 (m,2H) 1.99-2.09 (m, 2H) 1.83-1.99 (m, 5H) 1.65-1.83 (m, 4H) 1.55-1.65 (m,2H) 1.37-1.55 (m, 9H)

MS (m/z, MH+): 603.6

Step 2.

Preparation of7-Cycloheptyl-2-[5-(2,5-diaza-bicyclo[2.2.1]heptane-2-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Following deprotection method 1,5-[6-(7-Cycloheptyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylicacid tert-butyl ester (50 mg, 0.083 mmol, 1.0 eq) was converted to7-Cycloheptyl-2-[5-(2,5-diaza-bicyclo[2.2.1]heptane-2-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide as a white solid (24 mg, 0.05 mmol) in 57% yield. ¹HNMR (400 MHz, chloroform-d) δ ppm 8.89 (br s, 1H) 8.83 (br s, 1H)8.65-8.78 (m, 1H) 8.51-8.65 (m, 1H) 7.89-8.05 (m, 1H) 6.48 (s, 1H) 4.52(br s, 2H) 3.84-3.97 (m, 1H) 3.66-3.85 (m, 1H) 3.40-3.54 (m, 1H)3.24-3.40 (m, 1H) 3.19 (s, 6H) 2.67 (d, J=11.54 Hz, 2H) 2.03 (s, 3H)1.83-1.99 (m, 5H) 1.64-1.83 (m, 4H) 1.50-1.65 (m, 2H); HR-MS (m/z, MH+):503.2071.

Example 4

2-(5-(3,8-diazabicyclo[3.2.1]octane-3-carbonyl)pyridin-2-ylamino)-7-cycloheptyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

Step 1.

Preparation of tert-butyl3-(6-(7-cycloheptyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

Following amide formation method 1,6-(7-Cycloheptyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-nicotinicacid (75 mg, 0.178 mmol, 1.0 eq) was combined with tert-butyl3,8-diazabicyclo[3.2.1]octane-8-carboxylate (37.7 mg, 0.18 mmol, 1.0 eq)to give tert-butyl3-(6-(7-cycloheptyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylateas a white solid (80 mg, 0.130 mmol, 73% yield). ¹H NMR (400 MHz,chloroform-d) δ ppm 8.76 (s, 1H) 8.68 (d, J=8.59 Hz, 1H) 8.42-8.57 (m,1H) 8.40 (d, J=2.02 Hz, 1H) 7.83 (dd, J=8.59, 2.02 Hz, 1H) 6.49 (s, 1H)4.46-4.62 (m, 2H) 4.29 (br s, 2H) 3.19 (s, 6H) 2.56-2.73 (m, 2H)1.84-2.12 (m, 8H) 1.65-1.84 (m, 6H) 1.54-1.65 (m, 3H) 1.52 (s, 9H);

MS (m/z, MH+): 617.7.

Step 2.

Preparation of2-(5-(3,8-diazabicyclo[3.2.1]octane-3-carbonyl)pyridin-2-ylamino)-7-cycloheptyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

Following deprotection method 1, tert-butyl3-(6-(7-cycloheptyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylatewas converted to2-(5-(3,8-diazabicyclo[3.2.1]octane-3-carbonyl)pyridin-2-ylamino)-7-cycloheptyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamideas a white solid (60 mg, 0.116 mmol) in 96% yield. ¹H NMR (400 MHz,chloroform-d) δ ppm 8.68 (s, 1H) 8.60 (d, J=9.09 Hz, 1H) 8.32 (d, J=2.02Hz, 1H) 8.20 (s, 1H) 7.73 (dd, J=8.84, 2.27 Hz, 1H) 6.39 (s, 1H)4.33-4.57 (m, 2H) 3.10 (s, 6H) 2.45-2.68 (m, 2H) 1.86-2.00 (m, 3H) 1.79(br s, 7H) 1.56-1.73 (m, 7H) 1.40-1.56 (m, 3H); HR-MS (m/z, MH+):517.3027.

Example 5

2-(5-(2,7-diazaspiro[3.5]nonane-7-carbonyl)pyridin-2-ylamino)-7-cycloheptyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

Step 1.

Preparation of tert-butyl7-(6-(7-cycloheptyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinoyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate

Following general amide formation method 1,6-(7-Cycloheptyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-nicotinicacid (80 mg, 0.19 mmol, 1.0 eq) was combined with tert-butyl2,7-diazaspiro[3.5]nonane-2-carboxylate (47.1 mg, 0.208 mmol, 1.1 eq) toafford tert-butyl7-(6-(7-cycloheptyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinoyl)-2,7-diazaspiro[3.5]nonane-2-carboxylateas a white solid (22 mg, 0.035 mmol) in 18.4% yield. ¹H NMR (400 MHz,chloroform-d) δ ppm 8.67 (s, 1H) 8.60 (d, J=8.59 Hz, 1H) 8.31 (d, J=2.02Hz, 1H) 8.16-8.28 (m, 1H) 7.74 (dd, J=8.59, 2.53 Hz, 1H) 6.39 (s, 1H)5.23 (s, 1H) 4.38-4.51 (m, 1H) 3.63 (s, 4H) 3.52 (br s, 2H) 3.10 (s, 6H)2.48-2.66 (m, 2H) 1.86-2.03 (m, 2H) 1.56-1.85 (m, 9H) 1.42-1.56 (m, 4H)1.38 (s, 9H). MS (m/z, MH+): 631.7

Step 2.

Preparation of2-(5-(2,7-diazaspiro[3.5]nonane-7-carbonyl)pyridin-2-ylamino)-7-cycloheptyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

Following deprotection method 1, tert-butyl7-(6-(7-cycloheptyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinoyl)-2,7-diazaspiro[3.5]nonane-2-carboxylatewas converted to2-(5-(2,7-diazaspiro[3.5]nonane-7-carbonyl)pyridin-2-ylamino)-7-cycloheptyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamideas an off-white solid (25 mg, 0.05 mmol) in 69% yield. ¹H NMR (400 MHz,chloroform-d) δ ppm 9.05 (s, 1H) 8.48-8.59 (m, 1H) 8.04-8.13 (m, 1H)7.39-7.48 (m, 1H) 6.92 (s, 1H) 4.53-4.68 (m, 1H) 3.95 (s, 4H) 3.49-3.83(m, 4H) 3.18 (d, J=3.54 Hz, 6H) 2.46-2.69 (m, 2H) 2.03 (s, 10H)1.65-1.82 (m, 4H) 1.58 (none, 2H); HR-MS (m/z, MH+): 531.3199.

Example 6

7-cycloheptyl-2-(5-(8-hydroxy-8-methyl-3-azabicyclo[3.2.1]octane-3-carbonyl)pyridin-2-ylamino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

Step 1.

Preparation of 3-benzyl-8-methyl-3-azabicyclo[3.2.1]octan-8-ol

3-benzyl-3-azabicyclo[3.2.1]octan-8-one (200 mg, 0.93 mmol) wasdissolved in Et2O (2 ml) and added to a solution of MeMgBr (3 ml 1M Et2Osolution) in Et2O. The resulting reaction mixture was stirred at roomtemperature overnight. The mixture was diluted with Et2O and washed withsat. aq. NH4Cl solution and 1N NaOH. Aquoeus layers were backextractedwith Et2O. The combined organic layers were dried over Na2SO4, filteredand concentrated which gavebenzyl-8-methyl-3-azabicyclo[3.2.1]octan-8-ol (110 mg, 51% yield). 1HNMR (400 MHz, CDCl3) δ ppm 7.51-7.18 (m, 5H) 3.60 (br. s., 2H) 2.73 (d,J=10.11 Hz, 2H) 2.52 (d, J=9.60 Hz, 2H) 1.85 (br. s., 2H) 1.71 (br. s.,4H) 1.55 (br. s., 1H) 1.31 (s, 3H).

Step 2.

Preparation of 8-methyl-3-azabicyclo[3.2.1]octan-8-ol

A sample of 3-benzyl-8-methyl-3-azabicyclo[3.2.1]octan-8-ol (110 mg,0.48 mmol) was dissolved in MeOH (20 ml) and the atmosphere was replacedwith N2 (3×). 10% Pd/C (cat.) was added and the atmosphere was replacedwith H2 (3×). The resulting reaction mixture was stirred at RT atballoon pressure overnight. When TLC showed no more UV active spot thePd/C was filtered off (always keeping wet with MeOH) and the filtratewas concentrated which gave 8-methyl-3-azabicyclo[3.2.1]octan-8-ol (70mg, 99% yield).

NMR shows no more benzyl. Used directly.

Step 3.

Preparation of7-cycloheptyl-2-(5-(8-hydroxy-8-methyl-3-azabicyclo[3.2.1]octane-3-carbonyl)pyridin-2-ylamino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

Following general amide formation method 3,6-(7-cycloheptyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinicacid was combined with 8-methyl-3-azabicyclo[3.2.1]octan-8-ol which gave7-cycloheptyl-2-(5-(8-hydroxy-8-methyl-3-azabicyclo[3.2.1]octane-3-carbonyl)pyridin-2-ylamino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide(68 mg) in 26% yield. 1H NMR (400 MHz, CDCl3) δ ppm 9.65 (s, 1H)8.93-8.86 (m, 1H) 8.68 (d, J=8.59 Hz, 1H) 8.55 (d, J=2.02 Hz, 1H) 7.82(dd, J=8.84, 2.27 Hz, 1H) 6.52-6.39 (m, 1H) 4.45-4.60 (m, 1H) 4.39 (br.s., 1H) 3.96 (br. s., 1H) 3.63-3.39 (m, 2H) 3.15 (s, 6H) 2.76-2.51 (m,3H) 2.14 (br. s., 1H) 2.07-1.93 (m, 2H) 1.85 (ddd, J=6.95, 3.41, 3.28Hz, 3H) 1.80-1.61 (m, 7H) 1.61-1.48 (m, 2H) 1.48-1.36 (m, 1H) 1.30 (s,3H); HR-MS (m/z MH+) 546.32 RT 3.99 min.

Example 7

7-cycloheptyl-2-(5-((1R,4R,7R)-7-hydroxy-2-azabicyclo[2.2.1]heptane-2-carbonyl)pyridin-2-ylamino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

Following general amide formation method 3,6-(7-cycloheptyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinicacid was combined with (1R,4R,7R)-2-azabicyclo[2.2.1]heptan-7-ol whichgave7-cycloheptyl-2-(5-((1R,4R,7R)-7-hydroxy-2-azabicyclo[2.2.1]heptane-2-carbonyl)pyridin-2-ylamino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide(50 mg) in 77% yield.

1H NMR (400 MHz, CDCl3) δ ppm 9.79 (s, 0.8H, Rotamer) 9.58 (s, 0.2H,Rotamer) 8.93-8.82 (m, 1H) 8.76-8.55 (m, 2H) 7.90 (dd, J=8.84, 2.27 Hz,1H) 6.45 (s, 1H) 4.59-4.439 (m, 1H) 4.41 (br. s., 0.2H, Rotamer) 4.27(br. s., 0.2H, Rotamer) 4.20 (br. s., 0.8H, Rotamer) 4.06 (s, 0.8H,Rotamer) 3.73-3.57 (m, 2H) 3.07-3.39 (m, 7H) 2.75-2.54 (m, 2H) 2.42 (br.s., 0.8H, Rotamer) 2.35 (br. s., 0.2H, Rotamer) 2.20-1.93 (m, 4H)1.93-1.63 (m, 7H) 1.62-1.42 (m, 3H); HR-MS (m/z MH+) 518.29 RT 3.66 min

Example 8

2-(5-(8-acetyl-3,8-diazabicyclo[3.2.1]octane-3-carbonyl)pyridin-2-ylamino)-7-cycloheptyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

Following general amide formation method 3,6-(7-cycloheptyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinicacid was combined with 1-(3,8-diazabicyclo[3.2.1]octan-8-yl)ethanonewhich gave2-(5-(8-acetyl-3,8-diazabicyclo[3.2.1]octane-3-carbonyl)pyridin-2-ylamino)-7-cycloheptyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide(63 mg) in 88% yield. 1H NMR (400 MHz, CDCl3) δ ppm 9.69 (s, 1H) 8.90(s, 1H) 8.72 (d, J=8.59 Hz, 1H) 8.51 (d, J=2.02 Hz, 1H) 7.78 (dd,J=8.84, 2.27 Hz, 1H) 6.46 (s, 1H) 4.71 (br. s., 1H) 4.51 (tt, J=11.12,4.04 Hz, 1H) 4.16 (br. s., 1H) 3.24-3.10 (m, 7H) 2.70-2.55 (m, 2H)2.18-2.06 (m, 4H) 2.01 (ddd, J=13.64, 7.07, 4.04 Hz, 4H) 1.95-1.79 (m,5H) 1.79-1.62 (m, 5H) 1.62-1.49 (m, 2H). HR-MS (m/z MH+) 559.31 RT 3.89min.

Example 9

7-Cyclopentyl-2-[5-(3,6-diaza-bicyclo[3.2.1]octane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Step 1.

Preparation of3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-3,6-diaza-bicyclo[3.2.1]octane-6-carboxylicacid tert-butyl ester

Following general amide formation method 1,6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-nicotinicacid (in a salt form with 5 eq. of LiCl) (571 mg, 0.942 mmol) wascombined with tert-butyl 3,6-diazabicyclo[3.2.1]octane-6-carboxylate(200 mg, 0.942 mmol) to give 446 mg of3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-3,6-diaza-bicyclo[3.2.1]octane-6-carboxylicacid tert-butyl ester in 80% yield. MS (ESI) m/e (M+H⁺): 588.9.

Step 2.

Preparation of7-Cyclopentyl-2-[5-(3,6-diaza-bicyclo[3.2.1]octane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Following deprotection method 1,3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridin-3-carbonyl]-3,6-diaza-bicyclo[3.2.1]octane-6-carboxylicacid tert-butyl ester was converted to7-cyclopentyl-2-[5-(3,6-diaza-bicyclo[3.2.1]octane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide as the di-hydrochloride salt (275mg) in 72% yield. 1H NMR (400 MHz, DMSO-d₆) δ ppm 9.58 (1H, br. s.),9.01 (1H, s), 8.46 (1H, br. s.), 8.05 (1H, br. s.), 7.92 (1H, br. s.),6.88 (1H, s.), 4.80 (1H, quin.), 4.0 (1H, br. s), 3.57 (4H, br. s), 3.17(3H, br. s.), 3.07 (6H, s), 2.59-2.75 (1H, m), 2.35-2.45 (2H, br. m),1.84-2.09 (6H, m), 1.66-1.70 (2H, m). MS (ESI) m/e (M+H⁺): 489.9.

Step 3.

Separation of 215 mg of the approximate 1 to 1 mixture of enantiomers ofthe racemate7-Cyclopentyl-2-[5-(3,6-diaza-bicyclo[3.2.1]octane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide was done using the following conditions: As—H,4.6×100 mm, SFC, 4 g/min, 40 C, 30% MeOH 0.2% diethyl amine gaveapproximately 68 mg of each enantiomer7-cyclopentyl-2-[5-((1S,5S)-3,6-diaza-bicyclo[3.2.1]octane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide (isomer 1) and7-cyclopentyl-2-[5-((1R,5R)-3,6-diaza-bicyclo[3.2.1]octane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide (isomer 2)

Example 10

Enantiomer 1:7-Cyclopentyl-2-[5-((1S,5S)-3,6-diaza-bicyclo[3.2.1]octane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.02 (1H, s), 8.85 (1H, s), 8.32-8.38(2H, m), 7.86 (1H, br. s.), 6.66 (1H, s), 4.71-4.79 (1H, quin.),3.32-3.38 (4H, br. s.), 3.05-3.07 (6H, d), 2.86 (2H, br. s.), 2.72-2.74(1H, d), 2.33-2.55 (2H, m), 1.95-2.05 (4H, br. s.), 1.53-1.79 (4H, m),1.22-1.35 (2H, m)

MS (ESI) m/e (M+H⁺): 489.1

Example 11

Enantiomer 2:7-Cyclopentyl-2-[5((1R,5R)-3,6-diaza-bicyclo[3.2.1]octane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide 1H NMR (400 MHz, DMSO-d₆) δ ppm 10.03 (1H, br. s),8.85 (1H, s), 8.33-8.36 (2H, d), 7.85 (1H, br. s.), 6.66 (1H, s),4.72-4.80 (1H, quin.), 3.25-3.55 (5H, br. m), 3.06 (6H, d), 2.77-2.90(2H, br. s.), 2.37-2.60 (2H, m), 1.99 (4H, br. s), 1.66-1.79 (4H, m),1.24-1.37 (2H, br. s)

MS (ESI) m/e (M+H⁺): 489.0

Example 12

7-Cyclopentyl-2-{5-[6-(2,2,2-trifluoro-ethyl)-3,6-diaza-bicyclo[3.2.1]octane-3-carbonyl]-pyridin-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Preparation of7-Cyclopentyl-2-{5-[6-(2,2,2-trifluoro-ethyl)-3,6-diaza-bicyclo[3.2.1]octane-3-carbonyl]-pyridin-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

In a 100 ml round bottom flask was combined7-Cyclopentyl-2-[5-(3,6-diaza-bicyclo[3.2.1]octane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide (165 mg, 0.294 mmol) and DIPEA (0.128 ml, 0.735 mmol)which were diluted in Dioxane (6.00 ml) gave a yellowish heterogeneoussolution. To this mixture was then added potassium carbonate (406 mg,2.94 mmol) and trifluoroethyltriflate (0.106 ml, 0.735 mmol). Thereaction was heated to 50° C. for 18 h. LCMS showed 100% conversion. Themixture was diluted in DCM, and washed with sat'd aq solution of NaHCO3,followed by a brine wash. The organic layer was then separated, driedover MgSO4 and evaporated to give a yellowish solid. This solid wastriturated with EtOAc to give 98 mg of7-Cyclopentyl-2-{5-[6-(2,2,2-trifluoro-ethyl)-3,6-diaza-bicyclo[3.2.1]octane-3-carbonyl]-pyridin-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide in 58% yield. 1H NMR (400 MHz, DMSO-d₆) δ ppm 9.95(1H, s), 8.84 (1H, s), 8.30-8.40 (2H, m), 7.81-7.83 (1H, d), 6.65 (1H,s), 4.71-4.78 (1H, quin.), 3.23-3.42 (7H, m), 3.06 (7H, br. s.),2.30-2.45 (2H, br. s.), 1.99 (4H, br. s.), 1.55-1.75 (4H, d), 1.24-1.35(2H, br. s). MS (ESI) m/e (M+H⁺): 570.9

Example 13

7-Cyclopentyl-2-[5-(6-methyl-3,6-diaza-bicyclo[3.2.1]octane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Preparation of7-Cyclopentyl-2-[5-(6-methyl-3,6-diaza-bicyclo[3.2.1]octane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

In a 50 mL round-bottomed flask was combined7-Cyclopentyl-2-[5-(3,6-diaza-bicyclo[3.2.1]octane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide (183 mg, 0.326 mmol) and formaldehyde (37% solutionin water) (0.135 ml, 4.89 mmol) and in MeOH (4.00 ml)/DCM (4.00 ml) togive a yellowish solution. After 1.5 h stirring at room temperature,sodium triacetoxyborohydride (90 mg, 0.424 mmol) was added and thereaction was then stirred for another 12 h. LCMS showed completeconversion. The mixture was then diluted with dichloromethane, washedwith saturated aqueous solution of NaHCO3 followed by brine. Combinedorganic phases were then dried over MgSO4 and evaporated to give a lightyellow solid. Trituration with ethyl acetate then with dichloromethanefollowed by filtration gave 30 mg of7-Cyclopentyl-2-[5-(6-methyl-3,6-diaza-bicyclo[3.2.1]octane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide in 18% yield. 1H NMR (400 MHz, MeOD) δ ppm 8.81 (1H,s), 8.54 (2H, d), 8.42 (1H, s), 7.90 (1H, d, J=8.53 Hz), 6.66 (1H, s),4.91 (3H, s), 4.77-4.87 (1H, quin.), 3.30 (4H, br. s), 3.16-3.20 (7H,m), 2.65-2.90 (3H, br. s.), 2.50-2.60 (2H, m), 1.93-2.25 (5H, m), 1.76(2H, br. s). MS (ESI) m/e (M+H⁺): 502.9

Example 14

2-[5-(1-Amino-3-aza-bicyclo[3.1.0]hexane-3-carbonyl)-pyridin-2-ylamino]-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Step 1.

Preparation of{3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-3-aza-bicyclo[3.1.0]hex-1-yl}-carbamicacid tert-butyl ester

Following general amide formation method 1,6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-nicotinic(550 mg, 0.907 mmol) was combined with(3-Aza-bicyclo[3.1.0]hex-1-yl)-carbamic acid tert-butyl ester (180 mg,0.907 mmol) which gave 260 mg of{3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-3-aza-bicyclo[3.1.0]hex-1-yl}-carbamicacid tert-butyl ester in 50% yield.

MS (ESI) m/e (M+H⁺): 575.4

Step 2.

Preparation of2-[5-(1-amino-3-aza-bicyclo[3.1.0]hexane-3-carbonyl)-pyridin-2-ylamino]-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide di-hydrochloride

Following deprotection method 1,{3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-3-aza-bicyclo[3.1.0]hex-1-yl}-carbamicacid tert-butyl ester (250 mg, 0.435 mmol) was converted to2-[5-(1-amino-3-aza-bicyclo[3.1.0]hexane-3-carbonyl)-pyridin-2-ylamino]-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide di-hydrochloride (210 mg). 1H NMR (400 MHz, DMSO-d₆)δ ppm 9.04 (1H, s), 8.99 (1H, s), 8.53 (1H, s), 8.11 (1H, d), 7.83 (1H,br. 5.), 6.86 (1H, s), 4.75-4.84 (1H, quin.), 3.25-4.10 (6H, m), 3.07(6H, s), 2.24-2.40 (2H, d), 2.00-2.08 (5H, m), 1.65-1.67 (2H, d), 1.31(1H, br. s.), 0.82 (1H, br. s.); MS (ESI) m/e (M+H⁺): 475.1.

Step 3.

Separation of 200 mg of the approximate 1 to 1 mixture of enantiomers ofthe racemate2-[5-(1-Amino-3-aza-bicyclo[3.1.0]hexane-3-carbonyl)-pyridin-2-ylamino]-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide was done using the following conditions, As—H,4.6×100 mm, SFC, 4 g/min, 40 C, 45% MeOH 0.2% DEA in CO2 gaveapproximately 56 mg of each enantiomer2-[5-((S)-1-Amino-3-aza-bicyclo[3.1.0]hexane-3-carbonyl)-pyridin-2-ylamino]-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide and2-[5-((R)-1-Amino-3-aza-bicyclo[3.1.0]hexane-3-carbonyl)-pyridin-2-ylamino]-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide.

Example 15

Enantiomer 1: Preparation of2-[5-((S)-1-Amino-3-aza-bicyclo[3.1.0]hexane-3-carbonyl)-pyridin-2-ylamino]-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

1H NMR (400 MHz, DMSO-d₆) δ ppm 10.07 (1H, d), 8.86 (1H, s), 8.41 (1H,br. s.), 8.34-8.37 (1H, t), 7.88 (1H, d), 6.66 (1H, s), 4.73-4.80 (1H,quin.), 3.50-4.09 (2H, m), 3.20-3.45 (4H, br. s), 3.05-3.07 (6H, d),2.44 (2H, br. s.), 2.00 (4H, br. s.), 1.66 (2H, br. s.), 1.32 (1H, br.s.), 1.24 (1H, m), 0.38 (1H, br. s.); MS (ESI) m/e (M+H⁺): 475.4

Example 16

Enantiomer 2:2-[5-((R)-1-Amino-3-aza-bicyclo[3.1.0]hexane-3-carbonyl)-pyridin-2-ylamino]-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

1H NMR (400 MHz, DMSO-d₆) δ ppm 10.07 (1H, d), 8.86 (1H, s), 8.33-8.39(1H, t), 7.86-7.88 (1H, d), 6.66 (1H, s), 4.73-4.80 (1H, quin.),3.40-4.20 (2H, m), 3.25-3.37 (4H, m), 3.05-3.07 (6H, d), 2.44 (2H, br.s.), 2.00 (4H, br. s.), 1.66 (2H, br. s.), 1.24-1.37 (2H, m), 0.38 (1H,d). MS (ESI) m/e (M+H⁺): 475.3

Example 17

7-Cyclopentyl-2-[5-(1-dimethylamino-3-aza-bicyclo[3.1.0]hexane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Preparation of7-Cyclopentyl-2-[5-(1-dimethylamino-3-aza-bicyclo[3.1.0]hexane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

In a 50 mL round-bottomed flask was combined2-[5-(1-Amino-3-aza-bicyclo[3.1.0]hexane-3-carbonyl)-pyridin-2-ylamino]-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide (k) (200 mg, 0.421 mmol) and formaldehyde (37% inwater (0.967 ml, 10.54 mmol) in THF (3.000 ml)/methanol (3.000 ml)/DCM(3.000 ml) to give a yellowish suspension. After 2 h stirring at r.t.,sodium triacetoxyborohydride (223 mg, 1.054 mmol) was added and thereaction was stirred for another 16 h. Finally the reaction mixture waswashed with NaHCO3 and brine, dried over MgSO4 and evaporated to give alight brown solid. This solid was triturated with EtOAc to give 50 mg of7-Cyclopentyl-2-[5-(1-dimethylamino-3-aza-bicyclo[3.1.0]hexane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide (n) in 24% yield and >90% purity. 1H NMR (400 MHz,DMSO-d₆) δ ppm 10.01 (1H, br. s.), 8.86 (1H, br. s.), 8.45 (1H, d), 8.33(1H, t), 7.91 (1H, br. s.), 6.65 (1H, s), 4.69-4.90 (1H, quin.),3.75-3.92 (2H, m), 3.21-3.36 (3H, m), 3.06 (6H, br. s.), 2.40 (2H, br.s.), 2.29-2.35 (6H, d), 2.00 (4H, br. s.), 1.40-1.76 (2H, m), 1.36-1.43(1H, d), 0.46 (1H, br. s.); MS (ESI) m/e (M+W): 503.4

Example 18

7-Cyclopentyl-2-[5-(3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Step 1.

Preparation of3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester

Following general amide formation method 1,6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinicacid (400 mg, 1.01 mmol) was combined with3,8-Diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (250mg, 1.18 mmol. 1.1 eq) which yielded3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester after work up and was immediately used in nextstep without further purification.

MS m/z 589.7 (M+H)⁺.

Step 2.

Preparation of7-cyclopentyl-2-[5-(3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Following deprotection method 1,3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester was converted to7-cyclopentyl-2-[5-(3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide as a white solid (0.290 g, 0.594 mmol) in 59% yield.¹H NMR (400 MHz, CDCl₃) δ ppm 1.74 (m, 8H), 2.07 (m, 5H), 2.58 (m, 2H),3.50 (br 5, 2H), 3.17 (s, 7H), 4.81 (quin, J=8.8 Hz, 1H), 6.48 (s, 1H),7.79 (dd, J=8.8, 2.3 Hz), 8.30 (s, 1H), 8.39 (d, J=2.5 Hz, 1H), 8.56 (d,J=8.6 Hz, 1H), 8.77 (s, 1H);

MS m/z 489.6 (M+H)⁺.

Alternative Procedure for Example 18 Synthesis of7-Cyclopentyl-2-[5-(3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Step 1: Synthesis of6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinicacid

To a suspension of methyl6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinate(2.0 g, 4.9 mmol) in THF (6 mL) was added 1M LiOH (aq) (6 mL, 1.2 equiv)and the slurry stirred at 45° C. for 12 hours (the slurry became clear).After cooling to room temperature, the THF was evaporated and thereaction mixture was treated with 1 N HCl until pH=1-2. The resultingprecipitate was filtered and the filtrate extracted with 20%Isopropanol/CH₂Cl₂ (3×100 mL), the combined organic layers dried,filtered, and concentrated to a tan solid. The tan solid was trituratedin acetone giving the desired product as a tan solid (1.56 g, 73% yield)which was used without further purification. MS: (M+H)=395.5

Step 2: Synthesis of3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester

To a solution of6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinicacid (400 mg, 1.01 mmol) in DMF (5 mL) was addedO-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(HBTU, 580 mg, 1.53 mmol, 1.5 equiv) and N,N-diisopropylethylamine (0.55mL, 3.0 equiv) and the resulting mixture stirred at room temperature for5 minutes. To the reaction mixture was added3,8-Diaza-bicyclo[3.2.1]octane-8-carboxylic acid Pert-butyl ester (250mg, 1.18 mmol. 1.1 eq). The resulting mixture was stirred at roomtemperature for 30 minutes. The reaction mixture was diluted in EtOAc,washed with 0.5M HCl, water, dried over Na₂SO₄, filtered andconcentrated. Material was immediately used in next step without furtherpurification. MS: (M+H)=589.7

Step 3: Synthesis of the Title Compound

To a stirring solution of3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester (0.232 g, 1. mmol) in CH₂Cl₂ (4 mL) was added asolution of 4M HCl in dioxane (2.54 mL, 10.14 mmol, 10 eq) at 25° C.After 4 hours stirring at 25° C. the reaction mixture was filtered andwashed with CH₂Cl₂ (5 mL). The residue was collected and taken up inwater then basified with 1M NaOH and extracted with CH₂Cl₂ (2×15 mL).The combined organic layers were dried over Na₂SO₄, filtered, andconcentrated under reduced pressure to a tan solid. The crude waspurified using Column Chromatography (MeOH/CH₂Cl₂) giving the desiredproduct as a white solid (0.290 g, 0.594 mmol, 59%).

¹H NMR (400 MHz, CDCl₃)

8.77 (s, 1H), 8.56 (d, J=8.6 Hz, 1H), 8.39 (d, J=2.5 Hz, 1H), 8.30 (s,1H), 7.79 (dd, J=8.8, 2.3 Hz), 6.48 (s, 1H), 4.81 (quin, J=8.8 Hz, 1H),3.50 (br s, 2H), 3.17 (s, 7H), 2.58 (m, 2H), 2.07 (m, 5H), 1.74 (m, 8H);MS m/z 489.6 (M+H)⁺.

Example 19

7-Cyclopentyl-2-[5-((S,S)-2,5-diaza-bicyclo[2.2.1]heptane-2-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Step 1.

Preparation of5-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-(S,S)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylicacid tert-butyl ester

Following general amide formation method 1,6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinicacid (0.150 g, 0.380 mmol) was combined with(S,S)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester(100 mg, 0.504 mmol, 1.3 eq), which gave5-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-(S,S)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylicacid tert-butyl ester and used directly in the next step. MS m/z 575.7(M+H)⁺.

Step 2.

Preparation of7-Cyclopentyl-2-[5-((S,S)-2,5-diaza-bicyclo[2.2.1]heptane-2-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Following deprotection method 1,5-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-(S,S)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylicacid tert-butyl ester was converted to7-cyclopentyl-2-[5-((S,S)-2,5-diaza-bicyclo[2.2.1]heptane-2-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide as a white solid (55 mg, 0.110 mmol) in 29% yield. ¹HNMR (400 MHz, CDCl₃) δ ppm 1.91-2.14 (m, 5H), 2.43-2.62 (m, 2H),2.99-3.07 (m, 1H), 3.09 (s, 6H), 3.16 (d, J=10.11 Hz, 1H), 3.35 (d,J=11.12 Hz, 1H), 3.51-3.76 (m, 2H), 3.80 (br. s., 1H), 4.74 (quin,J=8.84 Hz, 1H), 6.41 (s, 1H), 7.77-7.96 (m, 1H), 8.41-8.56 (m, 2H),8.68-8.84 (m, 2H). MS m/z 475.5 (M+H)⁺.

Example 20

7-Cyclopentyl-2-[5-(hexahydro-pyrrolo[1,2-a]pyrazine-2-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Preparation of7-Cyclopentyl-2-[5-(hexahydro-pyrrolo[1,2-a]pyrazine-2-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Following general amide formation method 2,6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinicacid containing 5 eq of lithium Chloride (88 mg, 0.146 mmol) wascombined with octahydro-pyrrolo[1,2-a]pyrazine (0.050 mL, 0.264 mmol,1.6 eq) which gave after purification7-cyclopentyl-2-[5-(hexahydro-pyrrolo[1,2-a]pyrazine-2-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide as a white solid (40 mg, 0.077 mmol) in 29% yield. ¹HNMR (400 MHz, CD₂Cl₂) δ ppm 1.30 (br. s., 2H), 1.49 (s, 1H), 1.57-1.84(m, 6H), 1.88 (d, J=10.04 Hz, 2H), 2.00-2.20 (m, 5H), 2.35 (br. s., 2H),2.59 (dd, J=12.05, 9.03 Hz, 2H), 3.07-3.37 (m, 10H), 4.83 (quin, J=8.84Hz, 1H), 6.51 (s, 1H), 7.83 (dd, J=8.78, 2.26 Hz, 1H), 8.43 (d, J=2.01Hz, 2H), 8.59 (d, J=8.53 Hz, 1H), 8.82 (s, 1H)

HRMS calc for m/z=503.2883 and found m/z=503.2894 (M+H).

Example 21

7-Cyclopentyl-2-[5-((R)-hexahydro-pyrrolo[1,2-a]pyrazine-2-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Preparation of7-Cyclopentyl-2-[5-((R)-hexahydro-pyrrolo[1,2-a]pyrazine-2-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Following general amide formation method 2,6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinicacid containing 5 eq of lithium chloride (100 mg, 0.165 mmol) wascombined with (R)-octahydro-pyrrolo[1,2-a]pyrazine (40 mg, 0.317 mmol,1.9 eq) which gave after purification7-Cyclopentyl-2-[5-((R)-hexahydro-pyrrolo[1,2-a]pyrazine-2-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide as a white solid (60 mg, 0.113 mmol) in 69% yield. ¹HNMR (400 MHz, CDCl₃) δ ppm 1.20-1.33 (m, 2H), 1.69 (br. s., 3H),1.69-1.81 (m, 4H), 1.81-1.95 (m, 2H), 1.95-2.16 (m, 6H), 2.16-2.35 (m,2H), 2.48-2.68 (m, 2H), 3.08-3.15 (m, 2H), 3.15-3.23 (m, 7H), 4.80(quin, J=8.78 Hz, 2H), 6.48 (s, 1H), 7.82 (dd, J=8.78, 2.26 Hz, 1H),8.24 (s, 1H), 8.41 (d, J=2.01 Hz, 1H), 8.56 (d, J=8.53 Hz, 1H), 8.77 (s,1H); HRMS calc for m/z=503.2883 and found m/z=503.2898 (M+H).

Example 22

7-Cyclopentyl-2-[5-(3,8-diaza-bicyclo[3.2.1]octane-8-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Step 1.

Preparation of8-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-3,8-diaza-bicyclo[3.2.1]octane-3-carboxylicacid benzyl ester

Following general amide formation method 1,6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinic acid (700 mg, 1.78 mmol) was combined with3,8-diaza-bicyclo[3.2.1]octane-3-carboxylic acid benzyl ester (520 mg,2.11 mmol, 1.2 eq) (Reference: PCT Int. Appl., 2009067108, 28 May 2009)which gave after purification8-[6-(7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-3,8-diaza-bicyclo[3.2.1]octane-3-carboxylicacid benzyl ester as an off-white solid (550 mg, 0.839 mmol) in 47%yield. ¹H NMR (400 MHz, MeOD) δ ppm 1.66-1.86 (m, 2H) 1.91-2.18 (m, 8H)2.41-2.65 (m, 2H) 2.82 (br. s., 2H) 2.98 (br. s., 2H) 3.11-3.22 (m, 6H)4.17 (br. s., 1H) 4.64 (br. s., 1H) 4.74-4.84 (m, 1H) 6.65 (s, 1H) 7.92(dd, J=8.84, 2.27 Hz, 1H) 8.48 (d, J=2.53 Hz, 1H) 8.53 (d, J=9.60 Hz,1H) 8.82 (s, 1H); MS m/z 623.5 (M+H)⁺.

Step 2.

Preparation of7-Cyclopentyl-2-[5-(3,8-diaza-bicyclo[3.2.1]octane-8-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

A suspension of the8-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-3,8-diaza-bicyclo[3.2.1]octane-3-carboxylicacid benzyl ester (550 mg, 0.883 mmol) and 10% Pd/C (100 mg, 0.1 eq), inmethanol (10 mL) was evacuated and then purged with N₂ 3 times and thenbackfilled with hydrogen under balloon pressure and stirred for 16 hr.The reaction mixture was then filtered through a pad of Celite and thefiltrate concentrated to a colorless oil. To the oil was added ethylacetate/heptane and the resulting precipitate triturated which gave7-cyclopentyl-2-[5-(3,8-diaza-bicyclo[3.2.1]octane-8-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide as a white solid (260 mg, 0.532 mmol) in 60% yield.¹H NMR (400 MHz, MeOD) δ ppm 1.68-1.84 (m, 2H) 1.94-2.12 (m, 8H)2.12-2.18 (m, 1H) 2.45-2.61 (m, 2H) 2.77 (br. s., 2H) 2.93-3.11 (m, 2H)3.16 (s, 6H) 4.16 (br. s., 1H) 4.64 (br. s., 1H) 4.80 (t, J=8.84 Hz, 1H)6.64 (s, 1H) 7.92 (dd, J=8.59, 2.53 Hz, 1H) 8.47-8.57 (m, 2H) 8.85 (s,1H); MS m/z 489.9 (M+H)⁺.

Example 23

7-Cyclopentyl-2-[5-(3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid methylamide

Step 1.

Preparation of3-(6-Amino-pyridine-3-carbonyl)-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester

Following general amide formation method 1, 2-aminopyridyl-5-carboxylicacid (0.651 g, 4.71 mmol), was combined with3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (1.00g, 4.71 mmol) which gave after purification3-(6-Amino-pyridine-3-carbonyl)-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester as a white solid (0.780 g, 2.35 mmol) in 50%yield. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.42-1.54 (m, 17H) 1.67-1.87 (m,4H) 1.94 (br. s., 4H) 3.10 (br. s., 2H) 3.18 (br. s., 2H) 3.82 (d,J=12.63 Hz, 2H) 3.94 (br. s., 2H) 4.81 (br. s., 4H) 6.53 (d, J=8.59 Hz,2H) 7.67 (dd, J=8.59, 2.02 Hz, 2H) 8.28 (s, 2H); MS m/z 277.4 (M+H)⁺.

Step 2.

Preparation of3-[6-(7-Cyclopentyl-6-methylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester

Following general N—C coupling procedure 1,2-Chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acidmethylamide, see WO 2010020675, (0.150 g, 0.538 mmol) was combined with3-(6-amino-pyridine-3-carbonyl)-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester (0.188 g, 0.565 mmol, 1.05 eq), which gave3-[6-(7-cyclopentyl-6-methylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester as a yellow solid and was used directly in step 3.MS m/z 575.9 (M+H)⁺.

Step 3.

Preparation of7-cyclopentyl-2-[5-(3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid methylamide

Following deprotection method 1,3-[6-(7-cyclopentyl-6-methylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester was converted to7-cyclopentyl-2-[5-(3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid methylamide (60 mg, 0.126 mmol) in 24% yield. ¹H NMR (400 MHz,MeOD) δ ppm 1.68-1.87 (m, 3H) 1.92-2.04 (m, 3H) 2.04-2.19 (m, 7H)2.53-2.71 (m, 2H) 2.84 (d, J=12.63 Hz, 2H) 2.94 (s, 3H) 3.11 (br. s.,3H) 4.22 (br. s., 1H) 4.68 (br. s., 1H) 5.49 (quin, J=9.01, 8.84 Hz, 1H)6.87 (s, 1H) 7.91 (dd, J=8.59, 2.53 Hz, 1H) 8.46 (d, J=2.02 Hz, 1H) 8.58(d, J=8.59 Hz, 1H) 8.80 (s, 1H); MS m/z 475.1 (M+H)⁺.

Example 24

7-Cyclopentyl-2-[5-((S,S)-2,5-diaza-bicyclo[2.2.1]heptane-2-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid methylamide

Step 1.

Preparation of5-(6-Amino-pyridine-3-carbonyl)-(S,S)2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylicacid tert-butyl ester

Following general amide formation method 1, 2-aminopyridyl-5-carboxylicacid (0.697 g, 5.04 mmol), was combined with(S,S)-2,5-Diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester(1.00 g, 5.04 mmol, 1.0 eq) which after purification gave5-(6-Amino-pyridine-3-carbonyl)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylicacid tert-butyl ester as a white solid (350 mg, 1.01 mmol) in 20% yield.¹H NMR (400 MHz, CDCl₃) δ ppm 1.36-1.63 (m, 10H) 1.93 (br. s., 2H)3.34-3.86 (m, 4H) 4.35-5.07 (m, 3H) 6.55 (d, J=8.59 Hz, 1H) 7.71 (br.s., 1H) 8.29 (br. s., 1H); MS m/z 319.4 (M+H)⁺.

Step 2.

Preparation of(1S,4S)-5-[6-(7-Cyclopentyl-6-methylcarbamoyl-7H-pyrrolo[2,3-(1]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylicacid tert-butyl ester

Following general N—C coupling procedure 1,2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acidmethylamide, see WO 2010020675, (0.120 g, 0.431 mmol) was combined with(1S,4S)-5-(6-amino-pyridine-3-carbonyl)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylicacid tert-butyl ester (0.144 g, 0.452 g, 1.05 eq), which gave(1S,4S)-5-[6-(7-Cyclopentyl-6-methylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylicacid tert-butyl ester as a yellow solid. This material was used directlyin the following step 3. MS m/z 561.5 (M+H)⁺.

Step 3.

Preparation of7-Cyclopentyl-2-[5((1S,4S)-2,5-diaza-bicyclo[2.2.1]heptane-2-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid methylamide

Following deprotection method 1,(1S,4S)-5-[6-(7-Cyclopentyl-6-methylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester was converted to7-cyclopentyl-2-[5-((1S,4S)-2,5-diaza-bicyclo[2.2.1]heptane-2-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid methylamide (70 mg, 0.152 mmol) in 35% yield. ¹H NMR (400 MHz,MeOD) δ ppm 1.70-1.85 (m, 3H) 1.90 (s, 3H) 2.02-2.15 (m, 4H) 2.58 (d,J=9.09 Hz, 2H) 2.92 (s, 3H) 3.01 (t, J=9.35 Hz, 1H) 3.15 (dd, J=13.89,10.36 Hz, 1H) 3.39-3.50 (m, 1H) 3.66 (dd, J=11.37, 2.27 Hz, 1H)3.71-3.80 (m, 1H) 5.47 (quin, J=8.84 Hz, 1H) 6.88 (s, 1H) 7.83-8.02 (m,1H) 8.42-8.60 (m, 2H) 8.82 (s, 1H); MS m/z 461.5 (M+H)⁺.

Example 25

7-Cyclopentyl-2-[5((3aR,8aS)-octahydro-pyrrolo[2,3-c]azepine-7-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Step 1.

(3aR,8aS)-7-Phenethyl-octahydro-pyrrolo[2,3-c]azepine-1-carboxylic acidbenzyl ester

To a suspension of (3aR,8aS)-7-Phenethyl-decahydro-pyrrolo[2,3-c]azepine(4.0 g, 16.37 mmol) (Reference: PCT Int. Appl., 2005097791, 20 Oct.2005) in ethyl acetate (100 mL) was added a solution of potassiumcarbonate (6.79 g, 49.1 mmol, 3.0 eq) in water (100 mL). The biphasicsolution was cooled to 0° C. then benzylchloroformate (2.80 mL, 19.64mmol, 1.2 eq) added dropwise. The resulting mixture was stirred for 3 hrat 23° C. The mixture was partitioned and the aqueous layer extractedwith Ethyl Acetate. The combined organic layers were washed with waterfollowed by brine and the organic layer dried (Na₂SO₄), filtered, andthe filtrate concentrated to yield an orange oil. The crude was purifiedusing silica gel chromatography (1:2 Ethyl Acetate/Heptane to 100% EthylAcetate followed by 12:1 CH₂Cl₂/Methanol) giving(3aR,8aS)-7-Phenethyl-octahydro-pyrrolo[2,3-c]azepine-1-carboxylic acidbenzyl ester.

¹H NMR (400 MHz, CDCl₃) δ ppm 1.31-1.52 (m, 1H) 1.52-1.81 (m, 3H)1.81-2.03 (m, 2H) 2.25-2.53 (m, 3H) 2.53-2.68 (m, 2H) 2.68-2.97 (m, 3H)3.21-3.40 (m, 1H) 3.40-3.55 (m, 1H) 3.93-4.16 (m, 1H) 5.05 (d, J=12.05Hz, 1H) 5.13 (d, J=4.52 Hz, 1H) 7.04 (d, J=7.03 Hz, 1H) 7.12-7.30 (m,6H) 7.30-7.44 (m, 3H).

Step 2.

(3aR,8aS)-Octahydro-pyrrolo[2,3-c]azepine-1-carboxylic acid benzyl ester

To a solution of(3aR,8aS)-7-Phenethyl-octahydro-pyrrolo[2,3-c]azepine-1-carboxylic acidbenzyl ester (1.0 g, 2.64 mmol) in 1,2-dichloroethane (20 mL) was added1-chloroethyl carbonochloridate (0.286 mL, 2.64 mmol, 1.0 eq) at 0° C.The reaction was stirred with warming to 23° C. over 1 hr, then refluxedfor 3 hr. The solvent was removed in vacuo then 20 mL methanol added andthe reaction mixture heated to 50° C. for 1 hr. The reaction wasconcentrated and purified using chromatography (1:2 EthylAcetate/Heptane to 100% Ethyl Acetate followed by 12:1 CH₂Cl₂/Methanol)giving (3aR,8aS)-Octahydro-pyrrolo[2,3-c]azepine-1-carboxylic acidbenzyl ester.

MS m/z 379.3 (M+H)⁺.

Step 3.

7-Cyclopentyl-2-[5-((3aR,8a5)-octahydro-pyrrolo[2,3-c]azepine-7-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

A solution of6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinic acid (5 eq of Lithium Chloride) (0.088 g, 0.146 mmol), HBTU(0.086 mg, 0.226 mmol, 1.6 eq) and triethylamine (0.100 mL, 0.717 mmol,4.9 eq) in DMF (3 mL) was stirred at 23° C. for 5 minutes, then(3aR,8aS)-Octahydro-pyrrolo[2,3-c]azepine-1-carboxylic acid benzyl ester(0.040 mg, 0.146 mmol, 1.0 eq) was added and the reaction stirred at 23°C. for 1.5 hr. The reaction mixture was diluted with Ethyl Acetate, themixture washed with 0.5M HCl (aq), then water (3×), brine, the organiclayer dried (Na₂SO₄), filtered, and the filtrate concentrated. The crudewas purified using chromatography (Methanol/CH₂Cl₂) giving a whitesolid. To the resulting solid (42 mg) was added 10% Pd/C (15 mg)followed by methanol (5 mL). The suspension was blanketed with H₂balloon with stirring for 6 hr. The contents of the reaction werefiltered through Celite and the filtrate concentrated to a white solidthat was burified by trituration from Ethyl Acetate/Heptane followed bychromatography (methanol/CH₂Cl₂) mixtures gave7-cyclopentyl-2-[5-((3aR,8aS)-octahydro-pyrrolo[2,3-c]azepine-7-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide. (20 mg, 0.039 mmol, 27%). ¹H NMR (400 MHz, MeOD) δppm 1.62-1.84 (m, 5H) 1.84-1.99 (m, 2H) 1.99-2.20 (m, 4H) 2.31 (dd,J=13.05, 5.02 Hz, 1H) 2.47-2.62 (m, 2H) 2.63-2.80 (m, 1H) 3.18-3.27 (m,1H) 3.38-3.61 (m, 2H) 3.77 (d, J=13.05 Hz, 1H) 3.84-3.98 (m, 1H) 4.04(t, J=7.53 Hz, 1H) 4.06-4.19 (m, 1H) 4.80 (quin, J=9.03, 8.87 Hz, 1H)6.67 (s, 1H) 7.93 (dd, J=8.78, 2.26 Hz, 1H) 8.45 (d, J=2.01 Hz, 1H) 8.53(d, J=8.53 Hz, 1H) 8.82 (s, 1H); HRMS calc for m/z=517.3039 and foundm/z=517.3044 (M+H)⁺.

Example 26

7-cycloheptyl-2-(5-((1R,4R,7R)-7-hydroxy-2-azabicyclo[2.2.1]heptane-2-carbonyl)pyridin-2-ylamino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

The6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinicacid was combined with (1R,4R,7R)-2-azabicyclo[2.2.1]heptan-7-olfollowing amide formation method 3 which gave7-cycloheptyl-2-(5-((1R,4R,7R)-7-hydroxy-2-azabicyclo[2.2.1]heptane-2-carbonyl)pyridin-2-ylamino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide(47 mg, 78% yield). 1H NMR (400 MHz, CDCl3) δ ppm 9.75 (br. s., 0.8H,Rotamer) 9.60 (br. s., 0.2H, Rotamer) 8.88 (s, 1H) 8.60-8.50 (m, 1H)8.61-8.41 (m, 1H) 7.93-7.81 (m, 1H) 6.47 (s, 1H) 4.86-4.71 (m, J=8.97,8.97, 8.84, 8.59 Hz, 1H) 4.39 (br. s., 0.2H, Rotamer) 4.24 (br. s.,0.2H, Rotamer) 4.19 (br. s., 0.8H, Rotamer) 4.05 (s, 0.8H, Rotamer) 3.73(br. s., 0.8H, Rotamer) 3.67 (s, 0.2H, Rotamer) 3.65-3.62 (m, 0.8H,Rotamer) 3.46 (m, 0.2H, Rotamer) 3.24-3.21 (d, J=11.62 Hz, 0.8H,Rotamer) 3.16 (d, J=11.62 Hz, 0.2H, Rotamer) 3.15 (s, 6H) 2.66-2.6648(m, 2H) 2.41 (br. s., 0.8H, Rotamer) 2.34 (br. s., 0.2H, Rotamer)2.15-1.93 (m, 6H) 1.64-1.91 (m, 3H) 1.59-1.48 (m, 0.8H, Rotamer) 1.44(br. s., 0.2H, Rotamer); HR-MS (m/z MH+) 490.26 RT 3.21 min

Example 27

2-(5-(8-acetyl-3,8-diazabicyclo[3.2.1]octane-3-carbonyl)pyridin-2-ylamino)-7-cyclopentyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

The6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinicacid was combined with 1-(3,8-diazabicyclo[3.2.1]octan-8-yl)ethanonefollowing amide formation method 3 which gave2-(5-(8-acetyl-3,8-diazabicyclo[3.2.1]octane-3-carbonyl)pyridin-2-ylamino)-7-cyclopentyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide(43 mg, 62% yield). 1H NMR (400 MHz, MeOD) δ ppm 8.80 (s, 1H) 8.53 (d,J=8.59 Hz, 1H) 8.39 (d, J=2.02 Hz, 1H) 7.86 (dd, J=8.59, 2.02 Hz, 1H)6.65 (s, 1H) 4.80-4.73 (m, 1H) 4.73-4.25 (m, 3H) 3.86-3.41 (m, 2H) 3.16(s, 7H) 2.64-2.42 (m, 2H) 2.23-1.99 (m, 8H) 1.91 (br. s., 2H) 1.83-1.61(m, 3H); HR-MS (m/z MH⁺) 531.28 RT 4.27 min

Example 28

Preparation of7-cyclopentyl-2-(5-(8-(2-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octane-3-carbonyl)pyridin-2-ylamino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

The6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinicacid was combined with 2-(3,8-diazabicyclo[3.2.1]octan-8-yl)ethanolfollowing amide formation method 3 which gave7-cyclopentyl-2-(5-(8-(2-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octane-3-carbonyl)pyridin-2-ylamino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide(18 mg, 59% yield). 1H NMR (400 MHz, CDCl3) δ ppm 9.00-8.87 (m, 1H)8.87-8.78 (m, 1H) 8.57 (d, J=8.08 Hz, 1H) 8.44 (s, 1H) 7.79 (dd, J=8.59,2.53 Hz, 1H) 6.54-6.43 (m, 1H) 4.81 (dq, J=9.09, 8.93 Hz, 1H) 4.51 (br.s., 1H) 3.82-3.49 (m, 4H) 3.40-2.99 (m, 10H) 2.69-2.44 (m, 4H) 2.16-1.99(m, 4H) 1.91 (d, J=5.56 Hz, 2H) 1.83-1.45 (m, 4H); HR-MS (m/z MH+)533.30 RT 2.56 min

Example 29

7-cyclopentyl-2-(5-(8-isopropyl-3,8-diazabicyclo[3.2.1]octane-3-carbonyl)pyridin-2-ylamino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

To a solution of2-(5-(3,8-diazabicyclo[3.2.1]octane-3-carbonyl)pyridin-2-ylamino)-7-cyclopentyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide(42 mg, 0.086 mmol) in 6 ml of DCM, acetone (0.6 ml) was added and theresulting reaction mixture was stirred for 1H at room temperature.Na(AcO)₃BH (55 mg, 0.26 mmol) was added and the resulting reactionmixture was stirred at room temperature overnight. When LCMS showed thereaction was complete the reaction mixture was diluted with DCM, washedwith sat NaHCO3 (2×), brine. The combined aqueous layers werebackextracted with DCM and the combined organic layers were dried overNa2SO4, filtered and purified by column chromatography (0-20%MeOH/CHCl2) which gave7-cyclopentyl-2-(5-(8-isopropyl-3,8-diazabicyclo[3.2.1]octane-3-carbonyl)pyridin-2-ylamino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide(64 mg, 88% yield).

1H NMR (400 MHz, CDCl3) δ ppm 9.43 (br. s., 1H) 8.88 (s, 1H) 8.57 (d,J=8.59 Hz, 1H) 8.48 (d, J=2.53 Hz, 1H) 7.77 (dd, J=8.84, 2.27 Hz, 1H)6.47 (s, 1H) 4.80 (quip, J=8.84 Hz, 1H) 4.39 (br. s., 1H) 3.74-3.30 (m,4H) 3.26-3.04 (m, 7H) 2.68-2.49 (m, 3H) 2.18-1.95 (m, 4H) 1.86 (br. s.,2H) 1.79-1.62 (m, 3H) 1.53 (br. s., 1H) 1.07 (d, J=6.06 Hz, 6H)

HR-MS (m/z MH+) 531.32 RT 2.71 min

Example 30

7-cyclopentyl-2-(5-((1S,4S,5S)-5-hydroxy-2-azabicyclo[2.2.1]heptane-2-carbonyl)pyridin-2-ylamino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

The6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinicacid was combined with (1S,4S,5S)-2-azabicyclo[2.2.1]heptan-5-olfollowing amide formation method 3 which gave7-cyclopentyl-2-(5-((1S,4S,5S)-5-hydroxy-2-azabicyclo[2.2.1]heptane-2-carbonyl)pyridin-2-ylamino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide(40 mg, 63% yield). 1H NMR (400 MHz, CDCl3) δ ppm 9.84 (br. s., 0.4H,Rotamer) 9.54 (br. s., 0.6H, Rotamer) 8.98-8.82 (m, 1H) 8.80 (s, 0.4H,Rotamer) 8.59 (s, 0.6H, Rotamer) 8.57-8.48 (m, 1H) 7.97 (d, J=7.07 Hz,0.4H, Rotamer) 7.86 (d, J=6.57 Hz, 0.6H, Rotamer) 6.46 (s, 1H) 4.78 (m,1H) 4.74 (br. s., 0.4H, Rotamer) 4.46 (br. s., 1H) 4.17 (br. s., 0.6H,Rotamer) 4.07 (d, J=9.09 Hz, 0.4H, Rotamer) 3.91 (d, J=11.62 Hz, 0.6H,Rotamer) 3.64-3.49 (m, 0.6H, Rotamer) 3.49-3.269 (m, 1H+0.4H, Rotamer)3.15 (s, 6H) 2.73 (m, 0.6H, Rotamer) 2.67 (m, 0.4H, Rotamer) 2.57 (m,2H) 2.25-1.92 (m, 5H) 1.81-1.42 (m, 5H) HR-MS (m/z MH+) 490.26 RT 4.25min

Example 31

7-cyclopentyl-2-(5-((1S,4S,5R)-5-hydroxy-2-azabicyclo[2.2.1]heptane-2-carbonyl)pyridin-2-ylamino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

The6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinicacid was combined with (1S,4S,5R)-2-azabicyclo[2.2.1]heptan-5-olfollowing amide formation method 3 which gave7-cyclopentyl-2-(5-((1S,4S,5R)-5-hydroxy-2-azabicyclo[2.2.1]heptane-2-carbonyl)pyridin-2-ylamino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide(40 mg) in 60% yield. 1H NMR (400 MHz, CDCl3) δ ppm 9.51-9.43 (m, 0.3H,Rotamer) 9.43-9.35 (m, 0.7H, Rotamer) 8.87 (s, 1H) 8.66-8.60 (m, 0.3H,Rotamer) 8.60-8.52 (m, 0.7H, Rotamer+1H) 7.94-7.84 (m, 1H) 6.48 (s, 1H)4.86-4.75 (m, 1H) 4.75-4.71 (m, 0.3H, Rotamer) 4.32-4.25 (m, 0.7; H,Rotamer) 4.21-4.13 (m, 0.7H, Rotamer) 4.08-4.02 (m, 0.3H, Rotamer)3.61-3.50 (m, 1H) 3.15 (s, 6H) 3.10-3.01 (m, 1H) 2.93-2.83 (m, 0.7H,Rotamer) 2.78-2.67 (m, 0.3H, Rotamer H) 2.65-2.50 (m, 3H) 2.36-2.20 (m,1H) 2.15-1.99 (m, 4H) 1.99-1.88 (m, 1H) 1.80-1.65 (m, 2H) 1.59 (none,2H). HR-MS (m/z MH+) 490.26 RT 4.34 min

Example 32

7-cyclopentyl-N,N-dimethyl-2-(5-(octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

Step 1

Preparation of tert-butyl5-(6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate

The6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinicacid was combined with tert-butylhexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate following amideformation method 3 which gave tert-butyl5-(6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate(45 mg) in 63% yield. HR-MS (m/z MH+) 589.33 RT 4.31 min

Step 2

Preparation of7-cyclopentyl-N,N-dimethyl-2-(5-(octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

Following deprotection method 1, tert-butyl5-(6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (45 mg, 0.076 mmol) wasconverted to7-cyclopentyl-N,N-dimethyl-2-(5-(octahydropyrrolo[3,4-c]pyrrole-2-carbonyl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide(18 mg) in 48% yield. 1H NMR (400 MHz, CDCl3) δ ppm 9.18 (br. s., 1H)8.86 (s, 1H) 8.51-8.66 (m, 2H) 7.90 (dd, J=8.84, 2.27 Hz, 1H) 6.55-6.43(m, 1H) 4.81 (quin, J=8.84 Hz, 1H) 3.88 (br. s., 2H) 3.57 (br. s., 2H)3.24-3.05 (m, 8H) 2.95-2.68 (m, 4H) 2.68-2.51 (m, 2H) 2.44 (br. s., 1H)2.18-1.96 (m, 4H) 1.82-1.65 (m, 2H). HR-MS (m/z MH+) 489.27 RT 3.30 min

Example 33

7-cyclopentyl-2-(5-((1R,5S,8r)-8-hydroxy-3-azabicyclo[3.2.1]octane-3-carbonyl)pyridin-2-ylamino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

Preparation of7-cyclopentyl-2-(5-((1R,5S,8r)-8-hydroxy-3-azabicyclo[3.2.1]octane-3-carbonyl)pyridin-2-ylamino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

Following general amide formation method 3,6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinicacid was combined with 3-azabicyclo[3.2.1]octan-8-ol (for preparationsee WO 2007 040282) which gave7-cyclopentyl-2-(5-((1R,5S,8r)-8-hydroxy-3-azabicyclo[3.2.1]octane-3-carbonyl)pyridin-2-ylamino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide(50 mg) in 71% yield. 1H NMR (400 MHz, CDCl3) δ ppm 9.03 (s, 1H) 8.84(s, 1H) 8.56 (d, J=9.60 Hz, 1H) 8.48 (s, 1H) 7.80 (dd, J=8.84, 2.27 Hz,1H) 6.48 (s, 1H) 4.80 (quin, J=8.84 Hz, 1H) 4.38 (br. s., 1H) 4.08 (t,J=4.80 Hz, 1H) 3.87 (br. s., 1H) 3.55-3.38 (m, 2H) 3.16 (s, 6H) 2.68(br. s., 1H) 2.65-2.52 (m, J=11.81, 8.75, 8.75, 8.59 Hz, 2H) 2.21-1.91(m, 6H) 1.81-1.65 (m, 5H) 1.49 (br. s., 1H). HR-MS (m/z MH+) 504.27 RT3.55 min

Example 34

7-cyclopentyl-2-(5-(8-(dimethylamino)-3-azabicyclo[3.2.1]octane-3-carbonyl)pyridin-2-ylamino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

Step 1

Preparation of 3-benzyl-N,N-dimethyl-3-azabicyclo[3.2.1]octan-8-amine

To a solution of 3-benzyl-3-azabicyclo[3.2.1]octan-8-one (107 mg, 0.50mmol) in DCM (2 ml) was added dimethylamine (2 ml, 1M in THF) and theresulting reaction mixture was stirred at room temperature for 1H.Na(AcO)3BH (316 mg, 1.49 mmol) was added and the reaction mixture wasstirred at room temperature overnight. When TLC shows completionreaction mixture was diluted with DCM and washed with water and brine.Combined aqueous layers were backextracted with DCM. Combined organiclayers were dried over Na2SO4, filtered, concentrated and purified bycolumn chromatography which gave3-benzyl-N,N-dimethyl-3-azabicyclo[3.2.1]octan-8-amine (80 mg) in 67%yield. 1H NMR (400 MHz, MeOD) δ ppm 7.47-7.23 (m, 5H) 3.86 (s, 2H) 2.88(d, J=11.62 Hz, 2H) 2.72 (dd, J=12.38, 3.28 Hz, 2H) 2.52 (s, 7H) 2.35(br. s., 2H) 1.90-1.73 (m, 4H)

Step 2

Preparation of N,N-dimethyl-3-azabicyclo[3.2.1]octan-8-amine

3-benzyl-N,N-dimethyl-3-azabicyclo[3.2.1]octan-8-amine (80 mg, 0.45mmol) was dissolved in MeOH (10 ml) and the atmosphere was replaced withN2 (3×). 10% Pd/C (cat.) was added and the atmosphere was replaced withH2 (3×). The resulting reaction mixture was stirred at RT at balloonpressure overnight. When TLC showed no more UV active spot the Pd/C wasfiltered off (always keeping wet with MeOH) and the filtrate wasconcentrated which gave N,N-dimethyl-3-azabicyclo[3.2.1]octan-8-amine(44 mg) in 87% yield. 1H NMR (400 MHz, MeOD) δ ppm 3.45 (d, J=12.13 Hz,2H) 2.88 (dd, J=12.38, 2.78 Hz, 2H) 2.35 (d, J=2.02 Hz, 2H) 2.31-2.23(m, 6H) 2.11 (t, J=4.80 Hz, 1H) 2.06-1.92 (m, 2H) 1.89-1.79 (m, 2H)

Preparation of7-cyclopentyl-2-(5-(8-(dimethylamino)-3-azabicyclo[3.2.1]octane-3-carbonyl)pyridin-2-ylamino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

The6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinicacid was combined with N,N-dimethyl-3-azabicyclo[3.2.1]octan-8-aminefollowing amide formation method 3 which gave7-cyclopentyl-2-(5-(8-(dimethylamino)-3-azabicyclo[3.2.1]octane-3-carbonyl)pyridin-2-ylamino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide(12 mg) 14% yield. 1H NMR (400 MHz, CDCl3) δ ppm 8.82 (s, 1H) 8.76 (s,1H) 8.55 (d, J=9.60 Hz, 1H) 8.44 (d, J=2.02 Hz, 1H) 7.78 (dd, J=8.59,2.02 Hz, 1H) 6.48 (s, 1H) 4.87-4.73 (m, 1H) 4.31 (br. s., 1H) 3.75 (br.s., 1H) 3.35 (m, 2H) 3.16 (s, 6H) 2.68-2.51 (m, 2H) 2.30 (s, 7H)2.16-1.97 (m, 6H) 1.86-1.66 (m, 6H). HR-MS (m/z MH+) 531.32 RT 2.67 min

Example 35

7-cyclopentyl-2-(5-(8-(1-hydroxypropan-2-yl)-3,8-diazabicyclo[3.2.1]octane-3-carbonyl)pyridin-2-ylamino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

To a solution of2-(5-(3,8-diazabicyclo[3.2.1]octane-3-carbonyl)pyridin-2-ylamino)-7-cyclopentyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide(105 mg, 0.22 mmol) in dichloromethane (2 ml) 1-hydroxypropan-2-one (2ml) was added and the resulting reaction mixture was stirred for 1H atroom temperature. Sodium triacetoxyborohydride was added and thereaction mixture was stirred at room temperature overnight. WhenTLC/LCMS show completion the reaction mixture is diluted withdichloromethane, washed with sat NaHCO3 (2×) and brine. The combinedaqueous layers back extracted with dichloromethane and the combinedorganic layers are dried over sodium sulfate, filtered, concentrated andpurified by column chromatography (0-20% methanol/dichloromethane) whichgave7-cyclopentyl-2-(5-(8-(1-hydroxypropan-2-yl)-3,8-diazabicyclo[3.2.1]octane-3-carbonyl)pyridin-2-ylamino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide(39 mg, 33% yield). 1H NMR (400 MHz, CDCl3) δ ppm 9.07 (s, 1H) 8.85 (s,1H) 8.57 (d, J=9.09 Hz, 1H) 8.45 (s, 1H) 7.78 (dd, J=8.59, 2.53 Hz, 1H)6.48 (s, 1H) 4.81 (dq, J=9.09, 8.93 Hz, 1H) 4.48 (br. s., 1H) 3.75-3.30(m, 6H) 3.23-3.00 (m, 7H) 2.69-2.50 (m, 3H) 2.16-1.97 (m, 5H) 1.97-1.66(m, 6H) 1.10 (d, J=6.06 Hz, 3H); HR-MS (m/z MH+) 547.32 RT 2.54 min.

Example 36

7-(1R,2R,4S)-Bicyclo[2.2.1]hept-2-yl-2-[5-(3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Step 1

Preparation of6-(7-exo-bicyclo[2.2.1]hept-2-yl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-nicotinicacid methyl ester

Following general N—C coupling procedure 1,7-exo-bicyclo[2.2.1]hept-2-yl-2-chloro-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide (267 mg, 0.84 mmol), was combined with methyl6-aminonicotinate (140 mg, 0.92 mmol), which gave after purification6-(7-exo-bicyclo[2.2.1]hept-2-yl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-nicotinicacid methyl ester (364 mg) and used as is without furthercharacterization. MS m/z 435.5 (MH⁺)

Step 2

Preparations of6-(7-exo-Bicyclo[2.2.1]hept-2-yl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-nicotinicacid

To6-(7-exo-bicyclo[2.2.1]hept-2-yl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-nicotinicacid methyl ester (364 mg, 0.84 mmol) in tetrahydrofuran (25 mL), wasadded 5 ml of an aqueous solution of lithium hydroxide (176 mg, 4.19mmol). The mixture was heated to 60° C. for 18 hours, then cooled andthen acidified with 6N hydrochloric acid to pH 4. The resultant mixturewas then diluted with water and extracted with a 20% 2-propanol inchloroform solution (3×). The organic layer was washed with brine, thendried over anhydrous sodium sulfate, filtered and concentrated whichgave6-(7-exo-Bicyclo[2.2.1]hept-2-yl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-nicotinicacid as a brown powder and was used directly. ¹H NMR (400 MHz, DMSO-d

) δ 12.94 (br. s, 1H), 10.26 (s, 1H), 8.86 (s, 1H), 8.82 (s, 1H), 8.37(d, J=9.1 Hz, 1H), 8.22 (dd, J=9.1, 2.5 Hz, 1H), 6.68 (s, 1H), 4.37 (m,1H), 3.05 (5, 6 H), 2.85 (m, 1H), 2.67 (m, 1H), 2.36 (m, 1H) 1.80 (m,1H), 1.57 (m, 2H), 1.23 (m, 4H). MS m/z 421.5 (MH⁺),

Step 3

Preparation of3-[6-((1R,2R,4S)-7-Bicyclo[2.2.1]hept-2-yl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester

Following general amide formation method 1,6-(7-exo-Bicyclo[2.2.1]hept-2-yl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-nicotinicacid (100 mg, 0.24 mmol), was combined with3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (61mg, 0.29 mmol) which gave3-[6-((1R,2R,4S)-7-Bicyclo[2.2.1]hept-2-yl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester which was used directly without purification orfurther characterization.

Step 4

Following deprotection method 2,3-[6-((1R,2R,4S)-7-Bicyclo[2.2.1]hept-2-yl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester was converted to7-(1R,2R,4S)-Bicyclo[2.2.1]hept-2-yl-2-[5-(3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide (40 mg) in 33% yield. ¹H NMR (400 MHz, DMSO-d

) δ 9.87 (s, 1H), 8.81 (s, 1H), 8.28 (m, 2H), 7.81 (m, 1H), 6.65 (s,1H), 4.35 (m, 1H), 4.21 (br. s, 1H), 3.35 (m, 4H), 3.04 (s, 6H),2.88-2.85 (m, 2H), 2.65 (s, 1H), 2.35 (m, 1H) 1.81-1.75 (m, 1H),1.61-1.54 (m, 6H), 1.23 (m, 3H).

MS Mk 515.7 (MH⁺),

Example 37

7-(4-tert-Butyl-cyclohexyl)-2-[5-(3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Step 1

Preparation of3-{6-[7-(4-tert-Butyl-cyclohexyl)-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino]-pyridine-3-carbonyl}-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butylester

Following General N—C coupling procedure 1trans-7-(4-tert-butyl-cyclohexyl)-2-chloro-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide (157 mg, 0.43 mmol), was combined with3-(6-Amino-pyridine-3-carbonyl)-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester, which gave upon work up gave3-{6-[7-(4-tert-Butyl-cyclohexyl)-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino]-pyridine-3-carbonyl}-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butylester and was used as is.

Step 2

Preparation oftrans-7-(4-tert-Butyl-cyclohexyl)-2-[5-(3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Following deprotection method 2,3-(6-[7-(4-tert-Butyl-cyclohexyl)-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino]-pyridine-3-carbonyl)-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester was converted totrans-7-(4-tert-Butyl-cyclohexyl)-2-[5-(3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide (90 mg) in 37% yield. ¹H NMR (400 MHz, DMSO-d6) δ10.06 (s, 1H), 8.85 (s, 1H), 8.47-8.43 (m, 2H), 7.78 (dd, J=8.6, 2.5 Hz1H), 6.65 (s, 1H), 4.45 (m, 1H), 4.25 (m, 1H), 4.03 (m, 1H), 3.08 (s,3H), 3.05 (s, 3H), 2.83 (m, 2H), 2.61 (m, 4H), 1.94-1.81 (m, 8H), 1.15(m, 3H), 0.91 (s, 9H).

MS m/z 559.7 (MH⁺)

Example 38

7-Cyclopentyl-2-[6-(3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl)-pyridazin-3-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Step 1

Preparation of3-(6-Amino-pyridazine-3-carbonyl)-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester

Following general amide formation method 1,6-amino-pyridazine-3-carboxylic acid (212 mg, 1.0 mmol) was combinedwith 3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester(139 mg, 1.0 mmol), which gave3-(6-Amino-pyridazine-3-carbonyl)-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester as a white solid (169 mg, 0.51 mmol) in 51% yield.MS m/z 334.4 (M+H)⁺.

Step 2

Preparation of3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridazine-3-carbonyl]-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester

Following general N—C coupling procedure 1,2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic aciddimethylamide (98 mg, 0.336 mmol), was combined with3-(6-amino-pyridazine-3-carbonyl)-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester (112 mg, 0.336 mmol) which gave3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridazine-3-carbonyl]-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester (115 mg, 0.195 mmol) in 58% yield. MS m/z 590.6(M+H)⁺.

Step 3

Preparation of7-Cyclopentyl-2-[6-(3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl)-pyridazin-3-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Following deprotection method 2,3-[6-(7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridazine-3-carbonyl]-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester (110 mg, 0.187 mmol) was converted to7-Cyclopentyl-2-[6-(3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl)-pyridazin-3-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide as a white solid (55 mg, 0.112 mmol) in 60% yield. ¹HNMR (400 MHz, DMSO): δ, 10.71 (s, 1H), 8.88 (s, 1H), 8.60 (d, J=8 Hz,1H), 7.82 (d, J=8 Hz, 1H), 6.68 (s, 1H), 4.81-4.72 (m, 1H), 4.22 (d,J=12 Hz, 1H), 3.53 (d, J=12 Hz, 1H), 3.48 (br s, 1H), 3.29 (br s, 1H),3.27 (d, J=12 Hz, 1H), 3.06 (s, 3H), 3.05 (s, 3H) 2.93 (d, J=12 Hz, 1H),2.42-2.33 (m, 2H), 2.01-1.96 (m, 4H), 1.72-1.58 (m, 6H). HRMS calcd forC25H31N9O2.H⁺ (M+H)⁺ 1490.2679. found 490.2676 (M+H)⁺.

Example 39

7-Cyclopentyl-2-(5-(9-hydroxy-1,5,7-trimethyl-3,7-diazabicyclo[3.3.1]nonane-3-carbonyl)pyridin-2-ylamino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

Preparation of7-Cyclopentyl-2-(5-(9-hydroxy-1,5,7-trimethyl-3,7-diazabicyclo[3.3.1]nonane-3-carbonyl)pyridin-2-ylamino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

Following amide formation method 1,6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinicacid with 5 equiv LiCl and1,3,5-trimethyl-3,7-diazabicyclo[3.3.1]nonan-9-ol were combined and gave7-cyclopentyl-2-(5-(9-hydroxy-1,5,7-trimethyl-3,7-diazabicyclo[3.3.1]nonane-3-carbonyl)pyridin-2-ylamino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide(266 mg) in 68% yield. ¹H NMR (400 MHz, CDCl₃) δ ppm 8.77 (s, 1H), 8.56(d, J=8.6 Hz, 1H), 8.33 (s, 1H), 8.17 (br s, 1H), 7.72 (d, J=8.6 Hz,1H), 6.49 (s, 1H), 4.81 (m, 2H), 3.74 (br m, 1H), 3.26 (s, 1H), 3.18 (s,6H), 3.07 (br m, 1H), 2.70-2.56 (m, 4H), 2.29 (br m, 3H), 2.19 (s, 3H),2.15-2.03 (m, 4H), 1.89 (m, 1H), 1.75 (m, 2H), 1.00 (br s, 3H), 0.83 (brs 3H)

HRMS m/z 561.3301 (M+H)⁺.

Example 40

2-(5-((1R,5S)-3-oxa-7,9-diazabicyclo[3.3.1]nonane-9-carbonyl)pyridin-2-ylamino)-7-cyclopentyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

Step 1

Preparation of2-(5-((1R,5S)-3-oxa-7,9-diazabicyclo[3.3.1]nonane-9-carbonyl)pyridin-2-ylamino)-7-cyclopentyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

Following general amide formation method 2,6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinicacid with 5 equiv LiCl and (1R,5S)-tert-butyl3-oxa-7,9-diazabicyclo[3.3.1]nonane-7-carboxylate were combined and gave(1R,5S)-tert-butyl9-(6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinoyl)-3-oxa-7,9-diazabicyclo[3.3.1]nonane-7-carboxylate(115 mg) in 85% yield. ¹H NMR (400 MHz, CDCl₃) δ ppm 8.78 (s, 1H), 8.60(d, J=9.09 Hz, 1H), 8.44 (d, J=2.02 Hz, 2H), 7.85 (dd, J1=8.59 Hz,J2=2.02 Hz, 1H), 6.49 (s, 1H), 4.82 (m, 1H), 4.59-3.75 (m, 6H), 3.17 (s,4H), 3.02 (s, 2H), 2.95 (s, 2H), 2.81 (m, 4H), 2.57 (m, 1H), 2.09 (m,4H), 1.75 (m, 1H), 1.49 (m, 9H) LCMS m/z 604.9 (M+H)⁺.

Step 2

Preparation of2-(5-((1R,5S)-3-oxa-7,9-diazabicyclo[3.3.1]nonane-9-carbonyl)pyridin-2-ylamino)-7-cyclopentyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

Following deprotection method 2, (1R,5S)-tert-butyl9-(6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinoyl)-3-oxa-7,9-diazabicyclo[3.3.1]nonane-7-carboxylatewas converted to2-(5-((1R,5S)-3-oxa-7,9-diazabicyclo[3.3.1]nonane-9-carbonyl)pyridin-2-ylamino)-7-cyclopentyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide(80 mg) was obtained in 83% yield. ¹H NMR (400 MHz, CDCl₃) δ ppm 8.82(s, 1H), 8.63 (d, J=8.6 Hz, 1H), 8.56 (s, 1H), 8.47 (d, J=2.0 Hz, 1H),7.87 (dd, J1=8.78 Hz, J2=2.26 Hz, 1H), 6.51 (s, 1H), 4.83 (m, 1H), 4.47(s, 1H), 4.09 (m, 4H), 3.77 (s, 1H), 3.45-3.21 (m, 4H), 3.19 (s, 6H),2.59 (m, 2H), 2.11 (m, 5H), 1.77 (m, 2H). HRMS m/z 505.2665 (M+H)⁺.

Example 41

2-(5-(2,6-diazaspiro[3.3]heptane-2-carbonyl)pyridin-2-ylamino)-7-cyclopentyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

Step 1

Preparation of tert-butyl6-(6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinoyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

Following amide formation method 1,6-(7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-nicotinicacid (199 mg, 0.5 mmol, 1.0 eq) and tert-butyl2,6-diazaspiro[3.3]heptane-2-carboxylate (100 mg, 0.5 mmol, 1.0 eq) werecombined and gave tert-butyl6-(6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinoyl)-2,6-diazaspiro[3.3]heptane-2-carboxylateas a white solid (214 mg, 0.37 mmol) in 74% yield. ¹H NMR (400 MHz,chloroform-d) δ ppm 8.79 (s, 1H) 8.53-8.66 (m, 2H) 8.08 (dd, J=8.84,2.27 Hz, 1H) 6.53 (s, 1H) 4.74-4.92 (m, 1H) 4.20-4.61 (m, 4H) 4.07-4.16(m, 4H) 3.18 (br s, 6H) 2.47-2.65 (m, 2H) 2.03-2.20 (m, 4H) 1.68-1.85(m, 3H) 1.46 (s, 9H). MS (m/z, MH+): 575.6

Step 2

Preparation of2-(5-(2,6-diazaspiro[3.3]heptane-2-carbonyl)pyridin-2-ylamino)-7-cyclopentyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

Following deprotection method 2, tert-butyl6-(6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinoyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate(120 mg, 0.21 mmol, 1.0 eq) was converted to2-(5-(2,6-diazaspiro[3.3]heptane-2-carbonyl)pyridin-2-ylamino)-7-cyclopentyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide(35 mg, 0.076 mmol) in 36% yield. ¹H NMR (400 MHz, chloroform-d) δ ppm8.89 (br. s., 1H) 8.84 (s, 1H) 8.66 (s, 1H) 8.58 (d, J=8.59 Hz, 1H) 8.05(dd, J=9.09, 2.53 Hz, 1H) 6.50 (s, 1H) 4.74-4.92 (m, J=9.09, 8.84, 8.72,8.72 Hz, 1H) 4.51 (br. s., 2H) 4.33 (br s, 2H) 3.83 (d, J=8.08 Hz, 4H)3.18 (s, 6H) 2.51-2.69 (m, 2H) 2.01-2.19 (m, 4H) 1.63-1.91 (m, 3H).HR-MS (m/z, MH+): 475.2584.

Example 42

2-[5-((1S,5R,6S)-6-Amino-3-aza-bicyclo[3.1.0]hexane-3-carbonyl)-pyridin-2-ylamino]-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Step 1:

Preparation{(1S,5R,6S)-3-[6-(7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-3-aza-bicyclo[3.1.0]hex-6-yl}-carbamicacid tert-butyl ester

Following general amide formation method 1,6-(7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-nicotinicacid (100 mg, 0.254 mmol, 1.0 eq) was combined with(1S,5R,6S)-(3-Aza-bicyclo[3.1.0]hex-6-yl)-carbamic acid tert-butyl ester(55.3 mg, 0.279 mmol, 1.1 eq) which gave{(1S,5R,6S)-3-[6-(7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-3-aza-bicyclo[3.1.0]hex-6-yl}-carbamicacid tert-butyl ester as an oil (165 mg) and was used directly withoutpurification. MS m/z 575.4 (M+H)⁺

Step 2:

Preparation of2-[5-((1S,5R,6S)-6-Amino-3-aza-bicyclo[3.1.0]hexane-3-carbonyl)-pyridin-2-ylamino]-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Following deprotection method 2,{(1S,5R,6S)-3-[6-(7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-3-aza-bicyclo[3.1.0]hex-6-yl}-carbamicacid tert-butyl ester was converted to2-[5-((1S,5R,6S)-6-Amino-3-aza-bicyclo[3.1.0]hexane-3-carbonyl)-pyridin-2-ylamino]-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide (76 mg) in 56% yield. 1H NMR (400 MHz, DMSO-d₆) δ ppm1.47 (br. s., 2H) 1.66 (br. s., 3H) 2.00 (br. s., 6H) 2.34-2.48 (m, 2H)2.69 (s, 1H) 3.06 (br. s., 7H) 3.36-3.53 (m, 2H) 3.75 (d, J=5.56 Hz, 1H)3.88 (d, J=12.13 Hz, 1H) 4.76 (quin, J=8.84 Hz, 1H) 6.65 (s, 1H) 7.87(dd, J=8.59, 2.53 Hz, 1H) 8.33 (d, J=8.59 Hz, 1H) 8.40 (d, J=2.02 Hz,1H) 8.85 (s, 1H) 9.95 (s, 1H). MS m/z 475.5 (M+H)⁺.

Example 43

7-Cyclopentyl-2-[5-((1S,3S,5R)-3-hydroxy-8-aza-bicyclo[3.2.1]octane-8-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Preparation of7-Cyclopentyl-2-[5-((1S,3S,5R)-3-hydroxy-8-aza-bicyclo[3.2.1]octane-8-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Following general amide formation method 1,6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-nicotinicacid (120 mg, 0.304 mmol, 1.0 eq) was combined with(1S,3S,5R)-8-Aza-bicyclo[3.2.1]octan-3-ol (46.4 mg, 0.365 mmol, 1.2 eq)which gave7-cyclopentyl-2-[5-((1S,3S,5R)-3-hydroxy-8-aza-bicyclo[3.2.1]octane-8-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide (110 mg) in 72% yield. 1H NMR (400 MHz, CDCl₃-d) δppm 1.58-1.71 (m, 2H) 1.79 (br. s., 2H) 1.88-2.11 (m, 8H) 2.22 (d,J=7.58 Hz, 3H) 2.42-2.58 (m, 2H) 3.08 (s, 6H) 4.16 (br. s., 2H) 4.72(quin, J=8.84 Hz, 2H) 6.40 (s, 1H) 7.81 (dd, J=8.59, 2.02 Hz, 1 H) 8.12(br. s., 1H) 8.38 (d, J=2.02 Hz, 1H) 8.47 (br. s., 1H) 8.68 (s, 1H). MSm/z 504.6 (M+H)⁺.

Example 44

7-Cyclopentyl-2-[5-((1S,3R,5R)-3-hydroxy-8-aza-bicyclo[3.2.1]octane-8-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Preparation of7-Cyclopentyl-2-[5-((1S,3R,5R)-3-hydroxy-8-aza-bicyclo[3.2.1]octane-8-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Following general amide formation method 1,6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-nicotinicacid was combined with (1S,3R,5R)-8-Aza-bicyclo[3.2.1]octan-3-ol whichgave7-cyclopentyl-2-[5-((1S,3R,5R)-3-hydroxy-8-aza-bicyclo[3.2.1]octane-8-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide.

Example 45

7-cyclopentyl-2-[5-(8-methyl-3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Preparation of7-cyclopentyl-2-[5-(8-methyl-3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Following general amide formation method 1,6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-nicotinicacid (100 mg, 0.254 mmol, 1.0 eq) was combined with8-Methyl-3,8-diaza-bicyclo[3.2.1]octane (55.5 mg, 0.279 mmol, 1.1 eq)which gave7-cyclopentyl-2-[5-(8-methyl-3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide as solid (77 mg) in 60% yield. 1H NMR (400 MHz,DMSO-d₆) δ ppm 1.56-1.76 (m, 4H) 2.01 (br. s., 6H) 2.44 (br. s., 4H)3.06 (br. s., 8H) 3.33 (br. s., 4H) 3.49 (br. s., 4H) 4.76 (quin, J=8.84Hz, 1H) 6.66 (s, 1H) 7.82-7.88 (m, 1H) 8.33-8.41 (m, 2H) 8.85 (s, 1H)10.05 (s, 1H)

MS m/z 503.6 (M+H)⁺.

Example 46

2-[5-(7-Benzyl-9-oxa-3,7-diaza-bicyclo[3.3.1]nonane-3-carbonyl)-pyridin-2-ylamino]-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Preparation of2-[5-(7-Benzyl-9-oxa-3,7-diaza-bicyclo[3.3.1]nonane-3-carbonyl)-pyridin-2-ylamino]-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Following general amide formation method 1,6-(7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-nicotinicacid (200 mg, 0.507 mmol, 1.0 eq) was combined with3-benzyl-9-oxa-3,7-diaza-bicyclo[3.3.1]nonane (162 mg, 0.558 mmol, 1.1eq) (Reference: PCT Int. Appl. 2006137769, 2 Dec. 2006) which gave2-[5-(7-Benzyl-9-oxa-3,7-diaza-bicyclo[3.3.1]nonane-3-carbonyl)-pyridin-2-ylamino]-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide as solid (131 mg) in 39% yield. 1H NMR (400 MHz,CHLOROFORM-d) δ ppm 1.64-1.83 (m, 3H) 2.04 (d, J=7.07 Hz, 2H) 2.12 (d,J=6.57 Hz, 2H) 2.58 (br. s., 4H) 3.18 (s, 6H) 3.45 (br. s., 3H)3.49-3.57 (m, 1H) 3.67-3.80 (m, 1H) 3.84 (br. s., 2H) 4.02 (br. s., 1H)4.66-4.88 (m, 2H) 6.51 (s, 1H) 7.22-7.28 (m, 1H) 7.31-7.37 (m, 5H) 7.85(dd, J=8.84, 2.27 Hz, 1H) 8.27 (br. s., 1H) 8.43 (s, 1H) 8.51 (br. s.,1H) 8.78 (s, 1H). MS m/z 595.6 (M+H)⁺.

Example 47

7-Cyclopentyl-2-[5-(9-oxa-3,7-diaza-bicyclo[3.3.1]nonane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Step 1:

Preparation of7-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-9-oxa-3,7-diaza-bicyclo[3.3.1]nonane-3-carboxylicacid tert-butyl ester

Following general amide formation method 1,6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-nicotinicacid (266 mg, 0.438 mmol, 1.0 eq) was combined with9-Oxa-3,7-diaza-bicyclo[3.3.1]nonane-3-carboxylic acid tert-butyl ester(100 mg, 0.438 mmol, 1.0 eq) which gave7-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-9-oxa-3,7-diaza-bicyclo[3.3.1]nonane-3-carboxylicacid tert-butyl ester as a light pink powder (90 mg) in 34% yield. MSm/z 605.2 (M+H)⁺.

Step 2:

Preparation of7-Cyclopentyl-2-[5-(9-oxa-3,7-diaza-bicyclo[3.3.1]nonane-3-carbonyl)-pyridin-2-ylamino]-1-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Following deprotection method 2,7-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-9-oxa-3,7-diaza-bicyclo[3.3.1]nonane-3-carboxylicacid tert-butyl ester was converted to7-cyclopentyl-2-[5-(9-oxa-3,7-diaza-bicyclo[3.3.1]nonane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide (15 mg) in 18% yield. 1H NMR (400 MHz, CHLOROFORM-d)δ ppm 1.75 (d, J=6.06 Hz, 3H) 2.06-2.18 (m, 5H) 2.49-2.66 (m, 2H)3.03-3.14 (m, 2H) 3.18 (s, 6H) 3.42 (dd, J=12.63, 2.02 Hz, 2H) 3.63 (br.s., 1H) 3.81 (br. s., 2H) 4.83 (t, J=8.84 Hz, 1H) 6.50 (s, 1H) 7.85 (dd,J=8.59, 2.53 Hz, 1H) 8.42 (br. s., 1H) 8.45-8.51 (m, 1H) 8.60 (d, J=9.09Hz, 1H) 8.79 (s, 1H)

MS m/z 505.1 (M+H)⁺.

Example 48

7-Cyclopentyl-2-[5-(1,4-diaza-bicyclo[3.2.2]nonane-4-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Preparation of7-Cyclopentyl-2-[5-(1,4-diaza-bicyclo[3.2.2]nonane-4-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Following general amide formation method 1,6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-nicotinicacid (120 mg, 0.198 mmol, 1.0 eq) was combined with1,4-Diaza-bicyclo[3.2.2]nonane (43.3 mg, 0.218 mmol, 1.1 eq) which gave7-cyclopentyl-2-[5-(1,4-diaza-bicyclo[3.2.2]nonane-4-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide (25 mg) in 23% yield. 1H NMR (400 MHz, CDCl₃-d) δ ppm1.64-1.81 (m, 2H) 1.86 (br. s., 2H) 2.00-2.22 (m, 6H) 2.51-2.70 (m, 2H)3.03-3.16 (m, 5H) 3.18 (s, 7H) 3.79 (br. s., 2H) 4.83 (quin, J=8.84 Hz,1H) 6.50 (s, 1H) 7.81 (dd, J=8.84, 2.27 Hz, 1H) 8.35-8.44 (m, 2H) 8.58(d, J=8.59 Hz, 1H) 8.79 (s, 1H). HRMS m/z, (M+H)⁺: 503.2891

Example 49

7-Cyclopentyl-2-[5-((R,R)-2,5-diaza-bicyclo[2.2.1]heptane-2-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Step 1:

Preparation of5-(6-Amino-pyridine-3-carbonyl)-(R,R)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylicacid tert-butyl ester

Using amide formation method 1,(R,R)-2,5-Diaza-bicyclo[2.2.1]heptane-2-c arboxylic acid tert-butylester (1.0 g, 4.26 mmol, 1.0 eq) was combined with 6-Amino-nicotinicacid (588 mg, 4.26 mmol, 1.0 eq) to give5-(6-Amino-pyridine-3-carbonyl)-(R,R)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylicacid tert-butyl ester (420 mg, 31% yield). 1H NMR (400 MHz,CHLOROFORM-d) δ ppm 1.35-1.40 (m, 3H) 1.40-1.51 (m, 9H) 1.89 (br. s.,2H) 3.31-3.50 (m, 2H) 3.55 (d, J=9.09 Hz, 1H) 3.67 (dd, J=13.14, 6.57Hz, 1H) 4.50 (br. s., 1H) 4.64 (br. s., 1H) 4.91 (br. s., 1H) 6.51 (d,J=6.57 Hz, 1H) 7.64 (br. s., 1H) 8.24 (br. s., 1H); MS m/z 637.0 (M+H)⁺.

Step 2:

Preparation of5-[6-(7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-(R,R)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylicacid tert-butyl ester

Following general N—C coupling procedure 1,2-Chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic aciddimethylamide (200 mg, 0.683 mmol, 1.0 eq) was combined with5-(6-Amino-pyridine-3-carbonyl)-(R,R)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylicacid tert-butyl ester (217 mg, 0.683 mmol, 1.0 eq) which gave5-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-(R,R)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylicacid tert-butyl ester (100 mg) in 25% yield. 1H NMR (400 MHz, CDCl₃-d) δppm 1.47 (br. s., 5H) 1.52 (br. s., 5H) 1.69-1.83 (m, 2H) 1.83-2.00 (m,2H) 2.06-2.20 (m, 4H) 2.59 (br. s., 2H) 3.18 (s, 6H) 3.38-3.58 (m, 2H)3.58-3.82 (m, 3H) 4.56 (br. s., 1H) 4.75-4.91 (m, 1H) 6.50 (s, 1H) 7.96(br. s., 1H) 8.35 (br. s., 1H) 8.52 (br. s., 1H) 8.59 (br. s., 1H) 8.78(s, 1H)

HRMS m/z, (M+H)⁺: 575.3109.

Step 3:

Preparation of7-cyclopentyl-2-[5-((R,R)-2,5-diaza-bicyclo[2.2.1]heptane-2-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Following deprotection method 2,5-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-(R,R)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylicacid tert-butyl ester was converted to7-Cyclopentyl-2-[5-(R,R)-2,5-diaza-bicyclo[2.2.1]heptane-2-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide (20 mg) in 22% yield. 1H NMR (400 MHz, CHLOROFORM-d)δ ppm 1.65-1.85 (m, 4H) 2.03 (s, 2H) 2.06-2.19 (m, 6H) 2.59 (br. s., 2H)3.18 (s, 7H) 3.33 (d, J=9.60 Hz, 1H) 3.52 (br. s., 1H) 3.78 (br. s., 2H)4.72-4.94 (m, 1H) 6.38-6.54 (m, 1H) 7.96 (d, J=9.09 Hz, 1H) 8.56 (s, 1H)8.61 (d, J=8.59 Hz, 1H) 8.84 (br. s., 1H); HRMS m/z, (M+H)⁺: 475.2582.

Example 50

7-Cyclopentyl-2-[5-(3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl)-6-methyl-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Step 1:

Preparation of(3-(6-Amino-2-methyl-pyridine-3-carbonyl)-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester

Following general amide formation method 1,3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (279mg, 1.31 mmol, 1.0 eq) was combined with 6-amino-2-methylnicotinic acid(200 mg, 1.31 mmol, 1.0 eq) which gave3-(6-Amino-2-methyl-pyridine-3-carbonyl)-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester (400 mg) in 88% yield. MS m/z 346.6 (M+H)⁺.

Step 2:

Preparation of3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-2-methyl-pyridine-3-carbonyl]-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester

Following general N—C coupling procedure 1,2-Chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic aciddimethylamide (127 mg, 0.433 mmol, 1.0 eq) was combined with3-(6-Amino-2-methyl-pyridine-3-carbonyl)-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester (180 mg, 0.520 mmol, 1.2 eq) which gave3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-2-methyl-pyridine-3-carbonyl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester (70 mg) in 27% yield. 1H NMR (400 MHz,CHLOROFORM-d) δ ppm 1.51 (s, 10H) 1.61 (t, J=8.34 Hz, 1H) 1.68-1.81 (m,2H) 1.81-1.93 (m, 1H) 1.95-2.18 (m, 7H) 2.48 (br. s., 2H) 2.56 (d,J=8.59 Hz, 3H) 2.62 (br. s., 1H) 3.09 (d, J=7.58 Hz, 1H) 3.18 (s, 7H)3.26-3.36 (m, 1H) 3.40 (br. s., 1H) 4.17 (br. s., 1H) 4.37 (br. s., 1H)4.58 (d, J=13.14 Hz, 1H) 4.74-4.89 (m, J=9.09, 8.84, 8.72, 8.72 Hz, 1H)6.48 (s, 1H) 7.50 (br. s., 1H) 8.11 (br. s., 1H) 8.38 (d, J=8.08 Hz, 1H)8.76 (s, 1H). HRMS m/z, (M+H)⁺: 603.3417.

Step 3:

Preparation of7-Cyclopentyl-2-[5-(3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl)-6-methyl-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Following deprotection method 2,3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-2-methyl-pyridine-3-carbonyl]-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester was converted to7-cyclopentyl-2-[5-(3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl)-6-methyl-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide (36 mg) in 71% yield. 1H NMR (400 MHz, CDCl3-d) δ ppm1.61-1.79 (m, 3H) 1.79-1.97 (m, 3H) 1.97-2.18 (m, 5H) 2.50 (br. s., 3H)2.52-2.70 (m, 3H) 3.09 (d, J=12.63 Hz, 1H) 3.18 (s, 7H) 3.34 (q, J=11.79Hz, 2H) 3.46 (br. s., 1H) 3.69 (br. s., 1H) 4.55 (d, J=12.13 Hz, 1H)4.81 (quin, J=8.84 Hz, 1H) 6.48 (s, 1H) 7.49 (br. s., 1H) 8.03 (s, 1H)8.35 (d, J=8.59 Hz, 1H) 8.76 (s, 1H). HRMS m/z, (M+H)⁺: 503.2904.

Example 51

7-Cyclopentyl-2-[5-(3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl)-4-methyl-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Step 1:

Preparation of3-(6-Amino-4-methyl-pyridine-3-carbonyl)-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester

Following general amide formation method 1,3,8-Diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (279mg, 1.31 mmol, 1.0 eq) was combined with 6-Amino-4-methylnicotinic acid(200 mg, 1.31 mmol, 1.0 eq) to give3-(6-Amino-4-methyl-pyridine-3-carbonyl)-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester (251 mg) in 55% yield. MS m/z 347.0 (M+H)⁺.

Step 2:

Preparation of3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-4-methyl-pyridine-3-carbonyl]-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester

Following general N—C coupling procedure1,1,2-Chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic aciddimethylamide (140 mg, 0.479 mmol, 1.0 eq) was combined with3-(6-Amino-4-methyl-pyridine-3-carbonyl)-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester (199 mg, 0.574 mmol, 1.2 eq) which gave3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-4-methyl-pyridine-3-carbonyl]-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester (114 mg) in 38% yield. 1H NMR (400 MHz,CHLOROFORM-d) δ ppm 1.51 (s, 10H) 1.59 (d, J=9.60 Hz, 2H) 1.67-1.80 (m,2H) 1.80-1.90 (m, 1H) 1.99 (br. s., 2H) 2.07 (s, 4H) 2.42-2.66 (m, 5H)3.01-3.14 (m, 1H) 3.18 (s, 6H) 3.26-3.36 (m, 1H) 3.36-3.48 (m, 1H) 4.17(br. s., 1H) 4.36 (br. s., 1H) 4.58 (d, J=12.63 Hz, 1H) 4.75-4.88 (m,J=9.09, 8.84, 8.72, 8.72 Hz, 1H) 6.49 (s, 1H) 7.50 (br. s., 1H) 8.39(br. s., 1H) 8.75 (s, 1H)

HRMS m/z, (M+H)⁺: 603.3405.

Step 3:

Preparation of7-Cyclopentyl-2-[5-(3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl)-4-methyl-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Following deprotection method 2,3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-4-methyl-pyridine-3-carbonyl]-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester was converted to7-cyclopentyl-2-[5-(3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl)-4-methyl-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide (50 mg) in 57% yield. 1H NMR (400 MHz, CHLOROFORM-d)δ ppm 1.61-1.80 (m, 5H) 1.80-1.98 (m, 4H) 1.99-2.18 (m, 6H) 2.34-2.64(m, 7H) 3.08-3.23 (m, 10H) 3.27-3.38 (m, 2H) 3.38-3.47 (m, 1H) 3.50 (br.s., 1H) 4.57 (d, J=13.64 Hz, 1H) 4.81 (quin, J=8.84 Hz, 1H) 6.48 (s, 1H)7.48 (br. s., 1H) 7.99 (s, 1H) 8.36 (d, J=8.59 Hz, 1H) 8.75 (s, 1H)

HRMS m/z, (M+H)⁺: 503.2894.

Example 52

7-Cyclopentyl-2-[5-(3,9-diaza-bicyclo[3.3.1]nonane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Step 1:

Preparation of 3-Benzyl-3,9-diaza-bicyclo[3.3.1]nonane-9-carboxylic acidtert-butyl ester

To a solution of 3-benzyl-3,9-diaza-bicyclo[3.3.1]nonane (755 mg, 3.49mmol, 1.0 eq) in CH₂Cl₂ (10 mL) was added di-tert-butylcarbonate (990mg, 4.54 mmol, 1.3 eq) and triethylamine (0.730 mL, 5.24 mmol, 1.5 eq)and the mixture stirred for 16 hours at 23° C. The reaction mixture wasdiluted with CH₂Cl₂ and washed with water. The organic was collected anddried (Na₂SO₄), filtered, and concentrated to an oil. The crude waspurified using silica gel chromatography eluting with ethylacetate/heptane mixtures which gave the desired product as a colorlessoil (477 mg) in 41% yield. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.48 (s,9H) 1.51-1.64 (m, 1H) 1.64-1.75 (m, 2H) 1.75-1.93 (m, 2H) 2.21-2.39 (m,2H) 2.79-2.92 (m, 3H) 3.40 (s, 2H) 4.06 (br. s., 1H) 4.18 (br. s., 1H)7.21-7.30 (m, 1H) 7.34 (d, J=4.55 Hz, 4H).

Step 2:

Preparation of 3,9-Diaza-bicyclo[3.3.1]nonane-9-carboxylic acidtert-butyl ester

A mixture of benzyl-3,9-diaza-bicyclo[3.3.1]nonane-9-carboxylic acidtert-butyl ester (477 mg, 1.51 mmol, 1.0 eq) and palladium hydroxide oncarbon (466 mg) in ethanol (10 mL) was stirred with hydrogenation underballoon pressure until no more hydrogen uptake. The reaction was thenfiltered through celite and concentrated under reduced pressure. Thecrude was purified using chromatography (MeOH/Ethyl Acetate) which gave3,9-Diaza-bicyclo[3.3.1]nonane-9-carboxylic acid tert-butyl ester (170mg) in 47% yield. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.49 (s, 11H)1.57-1.70 (m, 1H) 1.70-1.79 (m, 2H) 1.79-2.01 (m, 2H) 2.43-2.58 (m,J=19.14, 12.69, 6.32, 6.32 Hz, 1H) 2.93-3.05 (m, 2H) 3.05-3.18 (m, 2H)3.99 (br. s., 1H) 4.11 (br. s., 1H)

Step 3:

Preparation of3-(6-Amino-pyridine-3-carbonyl)-3,9-diaza-bicyclo[3.3.1]nonane-9-carboxylicacid tert-butyl ester

Following general amide formation method1,3,9-diaza-bicyclo[3.3.1]nonane-9-carboxylic acid tert-butyl ester (170mg, 0.751 mmol, 1.1 eq) was combined with 6-amino-nicotinic acid (94 mg,0.683 mmol, 1.0 eq) which gave3-(6-amino-pyridine-3-carbonyl)-3,9-diaza-bicyclo[3.3.1]nonane-9-carboxylicacid tert-butyl ester (170 mg) in 72% yield. 1H NMR (400 MHz, CDCl₃-d) δppm 1.50 (s, 9H) 1.55-1.72 (m, 2H) 1.74-1.98 (m, 4H) 3.20 (qd, J=7.41,4.55 Hz, 3H) 3.65-3.82 (m, J=13.20, 6.66, 6.66, 4.29 Hz, 2H) 4.18 (br.s., 1H) 4.28 (br. s., 1H) 4.66 (br. s., 1H) 4.85 (br. s., 1H) 6.58 (d,J=8.59 Hz, 1H) 7.57 (dd, J=8.59, 2.02 Hz, 1H) 8.04 (s, 1H) 8.16 (d,J=2.02 Hz, 1H)

MS m/z 291.4 (M+H)⁺.

Step 4:

Preparation of3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-3,9-diaza-bicyclo[3.3.1]nonane-9-carboxylicacid tert-butyl ester

Following general N—C coupling procedure 1,2-Chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic aciddimethylamide (100 mg, 0.342 mmol, 1.0 eq) was combined with3-(6-Amino-pyridine-3-carbonyl)-3,9-diaza-bicyclo[3.3.1]nonane-9-carboxylicacid tert-butyl ester (130 mg, 0.376 mmol, 1.1 eq) which gave3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-3,9-diaza-bicyclo[3.3.1]nonane-9-carboxylicacid tert-butyl ester (121 mg) in 59% yield. 1H NMR (400 MHz,CHLOROFORM-d) δ ppm 1.51 (s, 10H) 1.56-1.70 (m, 3H) 1.70-1.81 (m, 3H)1.88 (br. s., 3H) 2.05-2.24 (m, 6H) 2.50-2.67 (m, 2H) 3.18 (s, 7H) 3.55(br. s., 1H) 3.91 (br. s., 1H) 4.25 (br. s., 1H) 4.78-4.90 (m, 1H) 6.50(s, 1H) 7.80 (dd, J=8.84, 2.27 Hz, 1H) 8.28 (br. s., 1H) 8.41 (s, 1H)8.59 (d, J=8.59 Hz, 1H) 8.78 (s, 1H); MS m/z 603.6 (M+H)⁺.

Step 5:

Following deprotection method 2,3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-3,9-diaza-bicyclo[3.3.1]nonane-9-carboxylicacid tert-butyl ester was converted to7-cyclopentyl-2-[5-(3,9-diaza-bicyclo[3.3.1]nonane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide (86 mg) in 96% yield. 1H NMR (400 MHz, CDCl₃-d) δ ppm1.71-1.82 (m, 3H) 2.02-2.21 (m, 8H) 2.60 (dd, J=12.13, 8.59 Hz, 2H) 3.18(s, 6H) 3.36 (br. s., 2H) 4.83 (quin, J=8.84 Hz, 1H) 6.50 (s, 1H) 7.82(dd, J=8.84, 2.27 Hz, 1H) 8.44 (s, 1H) 8.47 (s, 1H) 8.61 (d, J=8.59 Hz,1H) 8.81 (s, 1H)

HRMS m/z, (M+H)⁺: 503.2893.

Example 53

7-(4-tert-Butyl-phenyl)-2-[5-(3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Step 1:

Preparation of3-{6-[7-(4-tert-Butyl-phenyl)-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino]-pyridine-3-carbonyl}-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester

Following general N—C coupling procedure 1,7-(4-tert-Butyl-phenyl)-2-chloro-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide (100 mg, 0.280 mmol, 1.0 eq) was combined with3-(6-Amino-pyridine-3-carbonyl)-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester (93 mg, 0.280 mmol, 1.0 eq) which gave3-{6-[7-(4-tert-Butyl-phenyl)-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino]-pyridine-3-carbonyl}-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester (112 mg) in 58% yield. 1H NMR (400 MHz, DMSO-d₆) δppm 1.36 (s, 9H) 1.43 (s, 9H) 1.47-1.69 (m, 2H) 1.80 (br. s., 2H) 2.90(br. s., 3H) 3.05 (br. s., 3H) 4.12 (br. s., 2H) 6.92 (s, 1H) 7.41 (m,J=8.59 Hz, 2H) 7.59 (m, J=8.59 Hz, 2H) 7.68 (dd, J=8.84, 2.27 Hz, 1H)8.28-8.34 (m, 2H) 8.95 (s, 1H) 10.05 (s, 1H). MS m/z 653.7 (M+H)⁺.

Step 2:

Preparation of7-(4-tert-Butyl-phenyl)-2-[5-(3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Following deprotection method 2,3-{6-[7-(4-tert-Butyl-phenyl)-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino]-pyridine-3-carbonyl}-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester was converted to7-(4-tert-Butyl-phenyl)-2-[5-(3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide (67 mg) in 79%. 1H NMR (400 MHz, DMSO-d₆) δ ppm 1.32(s, 9H) 1.61 (br. s., 3H) 2.86 (br. s., 3H) 2.94 (br. s., 3H) 3.39 (br.s., 2H) 6.91 (s, 1H) 7.33-7.45 (m, 2H) 7.45-7.57 (m, 2H) 7.61 (dd,J=8.59, 2.53 Hz, 1H) 8.27 (d, J=2.02 Hz, 1H) 8.31 (d, J=9.09 Hz, 1H)8.96 (s, 1H) 10.04 (s, 1H). MS m/z 552.9 (M+H)⁺.

Example 54

7-(3-tert-Butyl-phenyl)-2-[5-(3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Step 1:

Preparation of3-{6-[7-(3-tert-Butyl-phenyl)-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino]-pyridine-3-carbonyl}-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester

Following general N—C coupling procedure 1,7-(3-tert-Butyl-phenyl)-2-chloro-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide (100 mg, 0.280 mmol, 1.0 eq) was combined with3-(6-Amino-pyridine-3-carbonyl)-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester (93 mg, 0.280 mmol, 1.0 eq) to give3-{6-[7-(3-tert-Butyl-phenyl)-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino]-pyridine-3-carbonyl}-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester (116 mg) in 60% yield. 1H NMR (400 MHz, DMSO-d₆) δppm 1.32 (s, 9H) 1.43 (s, 9H) 1.59 (br. s., 2H) 1.81 (br. s., 2H) 2.86(br. s., 3H) 2.94 (br. s., 3H) 4.12 (br. s., 2H) 6.91 (s, 1H) 7.37-7.43(m, 2H) 7.45-7.58 (m, 2H) 7.67 (dd, J=8.84, 2.27 Hz, 1H) 8.32 (dd,J=5.81, 2.78 Hz, 2H) 8.96 (s, 1H) 10.05 (s, 1H). MS m/z 653.7 (M+H)⁺.

Step 2:

Preparation of7-(3-tert-Butyl-phenyl)-2-[5-(3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Following deprotection method 2,3-{6-[7-(3-tert-Butyl-phenyl)-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino]-pyridine-3-carbonyl}-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester was converted to7-(3-tert-Butyl-phenyl)-2-[5-(3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide (75 mg) in 89%. 1H NMR (400 MHz, DMSO-d₆) δ ppm 1.36(5, 10 H) 1.60 (br. s., 2H) 1.70 (br. s., 2H) 2.90 (br. s., 3H) 3.05(br. s., 3H) 3.57 (br. s., 2H) 6.92 (s, 1H) 7.41 (m, J=8.59 Hz, 2H) 7.59(m, J=8.59 Hz, 2H) 7.66 (dd, J=8.84, 2.27 Hz, 1H) 8.29 (d, J=2.02 Hz,1H) 8.31 (d, J=8.59 Hz, 1H) 8.95 (s, 1H) 10.05 (s, 1H). MS m/z 552.9(M+H)⁺.

Example 55

7-(3-tert-Butyl-phenyl)-2-[5-(3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Step 1:

Preparation of3-[6-(7-Cyclobutyl-6-methylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester

Following general N—C coupling procedure 1,2-Chloro-7-cyclobutyl-7H-pyrrolo[2, 3-d]pyrimidine-6-carboxylic aciddimethylamide (200 mg, 0.718 mmol, 1.0 eq) was combined with3-(6-Amino-pyridine-3-carbonyl)-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester (262 mg, 0.789 mmol, 1.1 eq) to give3-[6-(7-Cyclobutyl-6-methylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester (218 mg, 50% yield). 1H NMR (400 MHz,CHLOROFORM-d) δ ppm 1.51 (s, 9H) 1.62 (br. s., 1H) 1.67 (br. s., 1H)1.77-2.07 (m, 6H) 2.41-2.58 (m, 2H) 3.17 (s, 6H) 3.19-3.29 (m, 2H) 3.64(br. s., 1H) 4.28 (br. s., 2H) 4.54 (br. s., 1H) 5.01 (dq, J=8.84, 8.67Hz, 1H) 6.50 (s, 1H) 7.83 (dd, J=8.84, 2.27 Hz, 1H) 8.42 (d, J=2.02 Hz,2H) 8.67 (d, J=9.09 Hz, 1H) 8.78 (s, 1H); MS m/z 574.9 (M+H)⁺.

Step: 2

Preparation of7-Cyclobutyl-2-[5-(3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Following deprotection method 2,3-[6-(7-Cyclobutyl-6-methylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester was converted to7-Cyclobutyl-2-[5-(3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide (128 mg) in 74%. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm1.78-2.08 (m, 10H) 2.45-2.57 (m, 2H) 3.17 (s, 6H) 3.20-3.31 (m, 3H) 3.56s., 3H) 4.53 (br. s., 1H) 5.01 (quin, J=8.84 Hz, 1H) 6.49 (s, 1H) 7.82(dd, J=8.59, 2.02 Hz, 1H) 8.43 (s, 1H) 8.60 (s, 1H) 8.67 (d, J=9.60 Hz,1H) 8.81 (s, 1H); MS m/z 474.9 (M+H)⁺.

Example 56

7-(3-tert-Butyl-phenyl)-2-[5-(3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Step 1:

Preparation of3-{6-[7-(1-Cyclopropyl-piperidin-4-yl)-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino]-pyridine-3-carbonyl}-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester

Using General Buchwald method 1,2-Chloro-7-(1-cyclopropyl-piperidin-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide (95 mg, 0.273 mmol, 1.0 eq) was combined with3-(6-Amino-pyridine-3-carbonyl)-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester (100 mg, 0.300 mmol, 1.1 eq) to give3-{6-[7-(1-Cyclopropyl-piperidin-4-yl)-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino]-pyridine-3-carbonyl}-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester (131 mg, 71% yield). 1H NMR (400 MHz,CHLOROFORM-d) δ ppm 0.46 (br. s., 2H) 0.54 (br. s., 2H) 1.52 (s, 10H)1.61 (br. s., 2H) 1.71 (br. s., 2H) 1.88 (d, J=10.11 Hz, 3H) 1.96 (d,J=6.06 Hz, 2H) 2.37 (t, J=11.62 Hz, 2H) 2.79-3.01 (m, 2H) 3.20 (s, 10H)3.63 (br. s., 2H) 4.27 (br. s., 2H) 4.41 (br. s., 2H) 6.50 (s, 1H) 7.69(br. s., 1H) 8.22 (s, 1H) 8.41 (s, 1H) 8.63 (d, J=8.59 Hz, 1H) 8.77 (s,1H); MS m/z 644.6 (M+H)⁺.

Step 2:

Preparation of7-(1-cyclopropyl-piperidin-4-yl)-2-[5-(3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Following deprotection method 2,3-{6-[7-(1-Cyclopropyl-piperidin-4-yl)-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino]-pyridine-3-carbonyl}-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester was converted to7-(1-Cyclopropyl-piperidin-4-yl)-2-[5-(3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide (25 mg) in 27%. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm0.44-0.62 (m, 4H) 1.28 (d, J=4.55 Hz, 2H) 1.75 (br. s., 1H) 1.91 (br.s., 3H) 2.02 (br. s., 2H) 2.41 (br. s., 2H) 2.93 (dd, J=12.38, 3.79 Hz,2H) 3.20 (s, 6H) 3.78 (br. s., 2H) 4.43 (t, J=12.38 Hz, 1H) 6.51 (s, 1H)7.71 (dd, J=8.59, 2.02 Hz, 1H) 8.44 (s, 1H) 8.46 (br. s., 1H) 8.64 (d,J=8.59 Hz, 1H) 8.79 (s, 1H); MS m/z 544.6 (M+H)⁺.

Example 57

7-(1-tert-Butyl-piperidin-4-yl)-2-[5-(3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Step 1:

Preparation of3-{6-[7-(1-tert-Butyl-piperidin-4-yl)-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino]-pyridine-3-carbonyl}-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester

Following general N—C coupling procedure 1, 1,7-(1-tert-Butyl-piperidin-4-yl)-2-chloro-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide (90 mg, 0.247 mmol, 1.0 eq) was combined with3-(6-Amino-pyridine-3-carbonyl)-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester (90 mg, 0.272 mmol, 1.1 eq) which gave3-{6-[7-(1-tert-Butyl-piperidin-4-yl)-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino]-pyridine-3-carbonyl)-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester (80 mg) in 47% yield. MS m/z 660.3 (M+H)⁺.

Step 2

Preparation of7-(1-tert-Butyl-piperidin-4-yl)-2-[5-(3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Following deprotection method 2,3-{6-[7-(1-tert-Butyl-piperidin-4-yl)-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino]-pyridine-3-carbonyl}-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester was converted to7-(1-tert-Butyl-piperidin-4-yl)-2-[5-(3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide (42 mg) in 59% yield. 1H NMR (400 MHz, DMSO-d₆) δ ppm1.09 (s, 9H) 1.55-1.66 (m, 2H) 1.77-1.87 (m, 2H) 2.09-2.15 (m, 2H)2.70-2.84 (m, 2H) 3.07 (d, J=11.12 Hz, 6H) 3.16 (d, J=10.61 Hz, 2H)4.18-4.28 (m, 1H) 6.66 (s, 1H) 7.70 (dd, J=8.84, 2.27 Hz, 1H) 8.30 (d,J=2.02 Hz, 1H) 8.59 (d, J=8.59 Hz, 1H) 8.84 (s, 1H) 9.96 (s, 1H). MS m/z560.6 (M+H)⁺.

Example 58

7-tert-Butyl-2-[5-(3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Step 1:

Preparation of3-[6-(7-tert-Butyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester

Following general N—C coupling procedure 1,7-tert-Butyl-2-chloro-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic aciddimethylamide (150 mg, 0.534 mmol, 1.0 eq) was combined with3-(6-Amino-pyridine-3-carbonyl)-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester (178 mg, 0.534 mmol, 1.0 eq) which gave3-[6-(7-tert-Butyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester (189 mg) in 61% yield. 1H NMR (400 MHz, DMSO-d₆) δppm 1.43 (s, 10H) 1.59 (br. s., 2H) 1.74-1.84 (m, 12 H) 3.00 (d, J=2.53Hz, 7H) 4.14 (br. s., 2H) 6.48 (s, 1H) 7.85 (dd, J=8.84, 2.27 Hz, 1H)8.28-8.39 (m, 2H) 8.80 (s, 1H) 9.89 (s, 1H). MS m/z 577.6 (M+H)⁺.

Step 2:

7-tert-Butyl-2-[5-(3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Following deprotection method 1,3-[6-(7-tert-Butyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester was converted to7-tert-Butyl-2-[5-(3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide (80 mg) in 48% yield. 1H NMR (400 MHz, DMSO-d₆) δ ppm1.46-1.69 (m, 4H) 1.78 (s, 9H) 3.00 (d, J=2.53 Hz, 6H) 3.42 (br. s., 4H)4.20 (br. s., 1H) 6.48 (s, 1H) 7.79 (dd, J=8.59, 2.53 Hz, 1H) 8.29-8.35(m, 2H) 8.80 (s, 1H) 9.86 (s, 1H). MS m/z 476.8 (M+H)⁺.

Example 59

2-{5-[8-((R)-2-Amino-4-methylsulfanyl-butyryl)-3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl]-pyridin-2-ylamino}-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Step 1:

Preparation of((R)-1-{3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-3,8-diaza-bicyclo[3.2.1]octane-8-carbonyl}-3-methylsulfanyl-propyl)-carbamicacid tert-butyl ester

Following general amide formation method1,7-Cyclopentyl-2-[5-(3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide (100 mg, 0.205 mmol, 1.0 eq) was combined withBOC-D-Methionine (51 mg, 0.205 mmol, 1.0 eq) which gave((R)-1-{3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-3,8-diaza-bicyclo[3.2.1]octane-8-carbonyl}-3-methylsulfanyl-propyl)-carbamicacid tert-butyl ester (105 mg) in 68% yield. 1H NMR (400 MHz,CHLOROFORM-d) δ ppm 1.39-1.56 (m, 14H) 1.63 (br. s., 2H) 1.68-1.82 (m,3H) 1.82-1.99 (m, 4H) 1.99-2.18 (m, 10H) 2.48-2.68 (m, 5H) 3.18 (s, 7H)3.73 (dd, J=10.36, 6.82 Hz, 1H) 4.51 (br. s., 1H) 4.69 (br. s., 3H)4.77-4.89 (m, 2H) 5.28 (t, J=10.11 Hz, 1H) 6.51 (s, 1H) 7.80 (d, J=6.57Hz, 1H) 8.36 (br. s., 1H) 8.42 (d, J=2.02 Hz, 1H) 8.59 (br. s., 1H) 8.80(s, 1H). HRMS m/z, (M+H)⁺: 720.3682.

Step 2:

Preparation of2-{5-[8-((R)-2-Amino-4-methylsulfanyl-butyryl)-3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl]-pyridin-2-ylamino}-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Following deprotection method 2,((R)-1-{3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-3,8-diaza-bicyclo[3.2.1]octane-8-carbonyl}-3-methylsulfanyl-propyl)-carbamicacid tert-butyl ester was converted to2-{5-[8-((R)-2-Amino-4-methylsulfanyl-butyryl)-3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl]-pyridin-2-ylamino}-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide (60 mg, 91%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm1.67-1.83 (m, 3H) 1.88 (br. s., 3H) 1.98-2.21 (m, 10H) 2.53-2.67 (m, 3H)2.67-2.84 (m, 2H) 3.18 (s, 7H) 3.84 (br. s., 1H) 3.95 (br. s., 1H) 4.45(br. s., 1H) 4.83 (dq, J=9.09, 8.93 Hz, 2H) 6.50 (s, 1H) 7.83 (d, J=6.57Hz, 1H) 8.44 (d, J=11.62 Hz, 1H) 8.53-8.66 (m, 1H) 8.85 (s, 1H). HRMSm/z, (M+H)⁺: 620.3113.

Example 60

2-{5-[8-(2-Amino-acetyl)-3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl]-pyridin-2-ylamino}-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Step 1:

Preparation of(2-{3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-3,8-diaza-bicyclo[3.2.1]oct-8-yl}-2-oxo-ethyl)-carbamicacid tert-butyl ester

Following general amide formation method 1,1,7-Cyclopentyl-2-[5-(3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide (100 mg, 0.205 mmol, 1.0 eq) was combined withBOC-Glycine (39.4 mg, 0.225 mmol, 1.1 eq) which gave(2-{3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-3,8-diaza-bicyclo[3.2.1]oct-8-yl}-2-oxo-ethyl)-carbamicacid tert-butyl ester (71 mg) in 53% yield. 1H NMR (400 MHz,CHLOROFORM-d) δ ppm 1.39 (s, 9H) 1.42-1.59 (m, 1H) 1.59-1.75 (m, 3H)1.85 (d, J=7.58 Hz, 2H) 2.00 (dd, J=14.65, 7.58 Hz, 5H) 2.41-2.60 (m,2H) 3.09 (s, 6H) 3.89 (br. s., 2H) 4.12 (br. s., 1H) 4.53-4.81 (m, 2H)5.35 (br. s., 1H) 6.42 (s, 1H) 7.71 (dd, J=8.84, 2.3 Hz, 1H) 8.31 (d,J=2.0 Hz, 1H) 8.48 (d, J=8.59 Hz, 1H) 8.69 (s, 1H); HRMS m/z, (M+H)⁺:646.3467.

Step 2:

Preparation of2-{5-[8-(2-Amino-acetyl)-3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl]-pyridin-2-ylamino}-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Following deprotection method 2,(2-{3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-3,8-diaza-bicyclo[3.2.1]oct-8-yl}-2-oxo-ethyl)-carbamicacid tert-butyl ester was converted to2-{5-[8-(2-amino-acetyl)-3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl]-pyridin-2-ylamino}-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide (48 mg) in 89% yield. 1H NMR (400 MHz, CHLOROFORM-d)δ ppm 1.06 (s, 3H) 1.37 (s, 2H) 1.46 (br. s., 3H) 1.62 (br. s., 2H) 1.82(d, J=17.68 Hz, 5H) 2.30 (br. s., 3H) 2.86-2.97 (m, 6H) 3.79 (br. s.,2H) 3.98 (br. s., 1H) 4.43 (br. s., 2H) 4.49-4.69 (m, 1H) 6.27 (s, 1H)7.64 (br. s., 1H) 8.28 (br. s., 4H) 8.72 (br. s., 1H). HRMS m/z, (M+H)⁺:546.2932.

Example 61

7-Cyclopentyl-2-{5-[8-(pyrrolidine-2-carbonyl)-3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl]-pyridin-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Step 1:

Preparation of2-{3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-3,8-diaza-bicyclo[3.2.1]octane-8-carbonyl}-pyrrolidine-1-carboxylicacid tert-butyl ester

Following general amide formation method1,7-cyclopentyl-2-[5-(3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide (100 mg, 0.205 mmol, 1.0 eq) was combined withBOC-Proline (48.5 mg, 0.225 mmol, 1.1 eq) which gave2-{3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-3,8-diaza-bicyclo[3.2.1]octane-8-carbonyl}-pyrrolidine-1-carboxylicacid tert-butyl ester (95 mg) in 64% yield. 1H NMR (400 MHz,CHLOROFORM-d) δ ppm 1.36-1.57 (m, 12H) 1.63-1.86 (m, 5H) 1.91 (br. s.,4H) 1.99-2.29 (m, 10H) 2.45-2.67 (m, 2H) 3.18 (s, 7H) 3.43 (d, J=6.57Hz, 2H) 3.60 (br. s., 3H) 4.42 (br. s., 2H) 4.56 (br. s., 2H) 4.68-4.94(m, 2H) 6.53 (s, 1H) 7.83 (d, J=8.08 Hz, 1H) 8.41 (br. s., 1H) 8.58 (d,J=8.59 Hz, 1H) 8.76-8.80 (m, 1H). HRMS m/z, (M+H)⁺: 686.3769.

Step 2:

7-Cyclopentyl-2-{5-[8-(pyrrolidine-2-carbonyl)-3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl]-pyridin-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Following deprotection method 2,2-{3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-3,8-diaza-bicyclo[3.2.1]octane-8-carbonyl}-pyrrolidine-1-carboxylicacid tert-butyl ester was converted to7-cyclopentyl-2-{5-[8-(pyrrolidine-2-carbonyl)-3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl]-pyridin-2-ylamino}-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide (36 mg) in 65% yield. 1H NMR (400 MHz, CHLOROFORM-d)δ ppm 1.67-1.84 (m, 3H) 1.90 (dd, J=13.14, 6.57 Hz, 3H) 1.99-2.28 (m,10H) 2.45-2.69 (m, 3H) 3.19 (s, 6H) 3.38-3.67 (m, 3H) 4.31 (br. s., 1H)4.71 (br. s., 1H) 4.76-4.89 (m, 2H) 4.92 (dd, J=8.84, 6.82 Hz, 1H) 6.51(s, 1H) 7.87 (dd, J=8.84, 2.27 Hz, 1H) 8.63 (t, J=8.59 Hz, 1H) 8.86 (s,1H) HRMS m/z, (M+H)⁺: 586.3278.

Example 62

2-{5-[8-((R)-2-Amino-3-methyl-butyryl)-3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl]-pyridin-2-ylamino}-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Step 1:

Preparation of((R)-1-{3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-3,8-diaza-bicyclo[3.2.1]octane-8-carbonyl}-2-methyl-propyl)-carbamicacid tert-butyl ester

Following general amide formation method1,7-cyclopentyl-2-[5-(3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide (60 mg, 0.123 mmol, 1.0 eq) was combined withBOC-D-Valine (26.7 mg, 0.123 mmol, 1.0 eq) which gave((R)-1-{3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-3,8-diaza-bicyclo[3.2.1]octane-8-carbonyl}-2-methyl-propyl)-carbamicacid tert-butyl ester (82 mg) in 92% yield. HRMS m/z, (M+H)⁺: 688.3961.

Step 2:

Preparation of2-{5-[8-((R)-2-Amino-3-methyl-butyryl)-3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl]-pyridin-2-ylamino}-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide

Following deprotection method 2,((R)-1-{3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-3,8-diaza-bicyclo[3.2.1]octane-8-carbonyl}-2-methyl-propyl)-carbamicacid tert-butyl ester was converted to2-{5-[8-((R)-2-amino-3-methyl-butyryl)-3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl]-pyridin-2-ylamino}-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide (20 mg) in 28% yield. 1H NMR (400 MHz, CHLOROFORM-d)δ ppm 1.05 (d, J=6.06 Hz, 6H) 1.13 (br. s., 1H) 1.81 (d, J=6.06 Hz, 4H)1.99 (br. s., 4H) 2.13 (br. s., 6H) 2.65 (br. s., 3H) 2.87 (s, 8H) 3.23(s, 7H) 3.68 (br. s., 1H) 4.39 (br. s., 1H) 4.76 (br. s., 1H) 4.81-5.07(m, 2H) 6.55 (s, 1H) 7.87 (br. s., 1H) 8.47 (br. s., 1H) 8.67 (d, J=8.08Hz, 1H) 8.92 (br. s., 1H). HRMS m/z, (M+H)⁺: 588.3424.

Example 63

7-Cyclopentyl-2-[5-(8-methyl-d₃-3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Preparation of7-Cyclopentyl-2-[5-(8-methyl-d₃-3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

To a mixture of7-Cyclopentyl-2-[5-(3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide (111 mg, 0.227 mmol, 1.0 eq), Potassium Carbonate(37.7 mg, 0.273 mmol, 1.2 eq) in Acetonitrile (1 mL) was addedIodomethane-d₃ (0.021 mL, 0.341 mmol, 1.5 eq) and the mixture stirred at23° C. for 5 hours. The reaction mixture was diluted with Ethyl Acetateand water and the organics colected and dried (Na₂SO₄), filtered, andconcentrated. The residue was purified using chromatography (EthylAcetate/Heptane) which gave desired product (15 mg) in 12% yield. 1H NMR(400 MHz, CHLOROFORM-d) δ ppm 1.61-1.83 (m, 3H) 2.02-2.18 (m, 7H)2.46-2.68 (m, 2H) 3.18 (s, 7H) 3.35 (br. s., 1H) 3.42 (br. s., 2H) 3.60(d, J=7.58 Hz, 1H) 3.71 (br. s., 1H) 3.79 (br. s., 1H) 4.57 (br. s., 1H)4.83 (quin, J=8.84 Hz, 1H) 6.51 (s, 1H) 7.83 (dd, J=8.84, 2.27 Hz, 1H)8.50 (d, J=2.02 Hz, 1H) 8.60 (d, J=9.09 Hz, 1H) 8.85 (s, 2H). HRMS m/z,(M+H)⁺: 506.3029.

Example 64

3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid ethyl ester

Preparation of3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid ethyl ester

To a solution of7-cyclopentyl-2-[5-(3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide (100 mg, 0.205 mmol, 1.0 eq) andDiisopropylethylamine (0.071 mL, 0.409 mmol, 2.0 eq) in CH₂Cl₂ (5 mL)was added Ethyl Chloroformate (0.022 mL, 0.225 mmol, 1.1 eq) diluted in3.0 mL of CH₂Cl₂. The reaction mixture was stirred at 23° C. for 1 hourthen diluted with water. The organic was collected and dried overNa₂SO₄, filtered, and concentrated. The crude reaction was purifiedusing silica gel chromatography which gave3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid ethyl ester (25 mg) in 21% yield. 1H NMR (400 MHz, CHLOROFORM-d) δppm 1.22-1.37 (m, 4H) 1.60 (br. s., 2H) 1.69-1.82 (m, 3H) 1.97 (br. s.,3H) 2.04-2.20 (m, 4H) 2.56 (d, J=8.59 Hz, 2H) 3.19 (s, 6H) 3.60 (br. s.,2H) 4.21 (q, J=7.07 Hz, 2H) 4.36 (br. s., 2H) 4.56 (br. s., 1H) 4.83 (t,J=8.59 Hz, 1H) 6.52 (s, 1H) 7.82 (dd, J=8.59, 2.02 Hz, 1H) 8.39 (d,J=2.02 Hz, 1H) 8.59 (d, J=8.59 Hz, 1H) 8.77 (s, 1H). HRMS m/z, (M+H)⁺:561.2946.

Example 65

2-(5-(3,8-diazabicyclo[3.2.1]octane-3-carbonyl)pyridin-2-ylamino)-N,N-dimethyl-7-(tetrahydro-2H-pyran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

Step 1

Preparation of tert-Butyl3-(6-(6-(dimethylcarbamoyl)-7-(tetrahydro-2H-pyran-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

Following general N—C coupling procedure 1,2-chloro-N,N-dimethyl-7-(tetrahydro-2H-pyran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide(80 mg, 0.26 mmole) was combined with tert-butyl3-(6-aminonicotinoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (82mg, 0.26 mmole) which gave tert-butyl3-(6-(6-(dimethylcarbamoyl)-7-(tetrahydro-2H-pyran-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate(40 mg) in 25% yield. 1H NMR (400 MHz, CD₂Cl₂) δ 8.84 (s, 1H), 8.72-8.65(m, 1H), 8.42 (m, 1H), 7.89-7.82 (m, 1H), 6.56 (s, 1H), 4.63-4.52 (m,1H), 4.52-4.41 (m, 1H), 4.26 (br, 2H), 4.08-3.96 (m, 2H), 3.70-3.49 (m,3H), 3.16 (S, 6H), 3.23-3.02 (m, 1H), 3.03-2.88 (m, 1H), 2.18-2.07 (m,1H), 2.02-1.57 (m, 7H), 1.51 (s, 9H). HR-MS m/z 605.3201 (M+H)⁺

Step 2

Preparation of2-(5-(3,8-diazabicyclo[3.2.1]octane-3-carbonyl)pyridin-2-ylamino)-7-cycloheptyl-N,N-dimethyl-7-(tetrahydro-2H-pyran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

Following deprotection method 1, tert-Butyl3-(6-(6-(dimethylcarbamoyl)-7-(tetrahydro-2H-pyran-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinoyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate(35 mg, 0.058 mmole) was converted to2-(5-(3,8-diazabicyclo[3.2.1]octane-3-carbonyl)pyridin-2-ylamino)-N,N-dimethyl-7-(tetrahydro-2H-pyran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamideas a free base form (11 mg) in 37% yield. 1H NMR (400 MHz, CD₃OD) δ 8.80(s, 1H), 8.60-8.55 (m, 1H), 8.48-8.35 (m, 1H), 7.99-7.85 (m, 1H),6.93-6.71 (m, 1H), 4.59-4.35 (m, 2H), 4.04-3.95 (m, 2H), 3.63-3.50 (m,3H), 3.50-3.39 (m, 2H), 3.20 (s, 3H), 3.17 (s, 3H), 2.97-2.77 (m, 2H),2.15-1.96 (m, 2H), 1.93-1.74 (m, 5H), 1.70-1.56 (m, 1H); HR-MS m/z505.2657 (M+H)⁺

Example 66

7-Cyclohexyl-2-[5-(3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Step 1

Preparation of2-chloro-7-cyclohexyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic aciddimethylamide

Following General Procedure A,2-chloro-7-cyclohexyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic aciddimethylamide was synthesized (2.4 gm, 17% Overall Yield)

MS m/z 307.5 (M+H)⁺.

Step 2

Preparation of6-(7-Cyclohexyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-nicotinicacid methyl ester

Following general N—C coupling procedure 1,2-chloro-7-cyclohexyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic aciddimethylamide (800 mg, 2.61 mmol), was combined with 6-amino-nicotinicacid methyl ester (397 mg, 2.61 mmol) which gave6-(7-cyclohexyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-nicotinicacid methyl ester (720 mg, 1.70 mmol) in 65% yield. MS m/z 423.6 (M+H)⁺.

Step 3

Preparation of6-(7-Cyclohexyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-nicotinicacid. To a 25 mL solution of THF, water and MeOH (2:2:1) containing6-(7-cyclohexyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-nicotinicacid methyl ester (860 mg, 2.04 mmol) was added solid LiOH (244 mg, 10.2mmol). After stirring at 50° C. for 90 m, reaction was acidified to pH 6with 1M HCl and then partitioned into two phases with a mixture ofwater, isopropyl alcohol and chloroform. The organic layer was removedand concentrated to yield6-(7-cyclohexyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-nicotinicacid (805 mg, 1.97 mmol) in 97% yield. MS m/z 409.6 (M÷H)⁺.

Step 4

Preparation of3-[6-(7-Cyclohexyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester. To a 1 mL DMF solution of6-(7-cyclohexyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-nicotinicacid (50 mg, 0.122 mmol) was added DIPEA (32 mg, 0.043 mmol) and HBTU(49 mg, 0.129 mmol). After stirring for 15 m at room temperature3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (31.2mg, 0.147 mmol) was added and the reaction mixture was left to stir atroom temperature for 4 h. The reaction was quenched by pouring intobrine and extracted with EtOAc. The organic extracts were dried withNa₂SO₄, filtered and concentrated. The crude product was purified byNP-LC (Analogix, 10% MeOH in EtOAc) to yield3-[6-(7-cyclohexyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester (60 mg, 0.10 mmol). MS m/z 603.5 (M+H)⁺.

Step 5

Preparation of7-Cyclohexyl-2-[5-(3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Following deprotection method 2,3-[6-(7-Cyclohexyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester (105 mg, 0.174 mmol) was converted to7-cyclohexyl-2-[5-(3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide (78 mg, 0.155 mmol) in 89% yield. 1H NMR (400 MHz,DMSO-d₆) δ ppm 10.10 (s, 1H), 8.85 (s, 1H), 8.47 (d, J=9.03 Hz, 1H),8.33 (d, J=2.01 Hz, 1H), 7.80 (dd, J=8.78, 2.26 Hz, 1H), 6.66 (s, 1H),4.28 (m, 1H), 3.36 (br. s., 10H), 3.07 (d, J=14.56 Hz, 6H), 2.56 (m,1H), 1.85 (m, 3H), 1.74 (d, J=9.54 Hz, 1H), 1.65 (br. s., 4H), 1.33 (m,2H). MS m/z 503.5 (M+H)⁺.

Example 67

7-Cyclohexyl-2-[5-(2,5-diaza-bicyclo[2.2.1]heptane-2-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Step 1

Preparation of5-[2-(7-Cyclohexyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyrimidine-5-carbonyl]-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylicacid tert-butyl ester

Following general amide formation method 1,6-(7-cyclohexyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-nicotinicacid (50 mg, 0.122 mmol) was combined with2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (29.1mg, 0.147 mmol) which gave5-[2-(7-cyclohexyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyrimidine-5-carbonyl]-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylicacid tert-butyl ester (60 mg, 0.102 mmol) in 84% yield. MS m/z 589.5(M+H)⁺.

Step 2

Preparation of7-Cyclohexyl-2-[5-(2,5-diaza-bicyclo[2.2.1]heptane-2-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Following deprotection method 2,5-[2-(7-cyclohexyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyrimidine-5-carbonyl]-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylicacid tert-butyl ester (110 mg, 0.187 mmol) was converted to7-cyclohexyl-2-[5-(2,5-diaza-bicyclo[2.2.1]heptane-2-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide (78 mg, 0.160 mmol) in 86% yield. 1H NMR (400 MHz,DMSO-d₆) δ ppm 10.10 (s, 1H), 8.85 (s, 1H), 8.47 (d, J=9.03 Hz, 1H),8.33 (d, J=2.01 Hz, 1H), 7.80 (dd, J=8.78, 2.26 Hz, 1H), 6.76 (m, 0H),6.66 (s, 1H), 4.27 (m, 2H), 3.36 (br. s., 8H), 3.07 (d, J=14.56 Hz, 7H),1.85 (m, 5H), 1.71 (m, 6H), 1.33 (m, 4H). MS m/z 489.5 (M+H)⁺.

Example 68

7-[4-(Cyano-dimethyl-methyl)-phenyl]-2-[5-(3,8-diaza-bicyclo[3.2.1]octane-8-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Step 1

Preparation of3-(6-{7-[4-(Cyano-dimethyl-methyl)-phenyl]-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino}-pyridine-3-carbonyl)-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester

Following general N—C coupling procedure 1,2-chloro-7-[4-(cyano-dimethyl-methyl)-phenyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide (70 mg, 0.190 mmol) was combined with3-(6-amino-pyridine-3-carbonyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester (63.3 mg, 0.190 mmol) which gave3-(6-{7-[4-(cyano-dimethyl-methyl)-phenyl]-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino}-pyridine-3-carbonyl)-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester (63 mg, 0.095 mmol) in 50% yield. MS m/z 664.2(M+H)⁺.

Step 2

Preparation of7-[4-(Cyano-dimethyl-methyl)-phenyl]-2-[5-(3,8-diaza-bicyclo[3.2.1]octane-8-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Following deprotection method 2,3-(6-{7-[4-(cyano-dimethyl-methyl)-phenyl]-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino}-pyridine-3-carbonyl)-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester (63 mg, 0.095 mmol) was converted to7-[4-(cyano-dimethyl-methyl)-phenyl]-2-[5-(3,8-diaza-bicyclo[3.2.1]octane-8-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide. (48 mg, 0.085 mmol) in 89% yield. 1H NMR (400 MHz,DMSO-d₆) δ ppm 10.08 (s, 1H), 8.97 (s, 1H), 8.28 (m, 2H), 7.73 (d,J=8.59 Hz, 2H), 7.68 (dd, J=8.59, 2.53 Hz, 1H), 7.56 (d, J=8.59 Hz, 2H),6.97 (s, 1H), 3.41 (m, 4H), 3.01 (m, 8H), 1.77 (m, 5H), 1.63 (d, J=4.04Hz, 4H), 1.26 (m, 1H), 0.86 (s, 1H). MS m/z 564.5 (M+H)⁺.

Example 69

7-Cyclopentyl-2-[5-(3,9-diaza-bicyclo[4.2.1]nonane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Step 1

Preparation of3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-3,9-diaza-bicyclo[4.2.1]nonane-9-carboxylicacid tert-butyl ester

Following general amide formation method 3,6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinicacid (0.2 g, 0.507 mmol) was combined with3,9-diaza-bicyclo[4.2.1]nonane-9-carboxylic acid tert-butyl ester (0.136g, 0.6 mmol) which gave3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-3,9-diaza-bicyclo[4.2.1]nonane-9-carboxylicacid tert-butyl ester (0.269 g, 0.433 mmol) in 85% yield. MS m/z 602.7(M+H)⁺.

Step 2

Preparation of7-Cyclopentyl-2-[5-(3,9-diaza-bicyclo[4.2.1]nonane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Following deprotection method 1,3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-3,9-diaza-bicyclo[4.2.1]nonane-9-carboxylicacid tert-butyl ester (0.24 g, 0.398 mmol) was converted to7-Cyclopentyl-2-[5-(3,9-diaza-bicyclo[4.2.1]nonane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide (203 mg, 0.363 mmol) in 91.4% yield. 1H NMR (400 MHz,DMSO-d₆) δ ppm 11.7 (s, 1H), 10.18 (s, 1H), 9.05 (s, 1H), 8.52 (s, 1H),8.13 (d, 1H), 7.8 (d, 1H), 6.85 (s, 1H), 4.8 (m, 2H), 4.1 (m. broad,2H), 3.7 (m. broad, 2H), 3.06 (s, 3H), 3.05 (s, 3H), 2.3 (m. broad, 2H),2.25-1.7 (m. broad, 8H), 1.65 (m. broad, 2H). MS m/z 502.7 (M+H)⁺.

Example 70

7-Cyclopentyl-2-[5-(3-oxa-7,9-diaza-bicyclo[3.3.1]nonane-7-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Step 1

Preparation of7-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-3-oxa-7,9-diaza-bicyclo[3.3.1]nonane-9-carboxylicacid benzyl ester

Following general amide formation method 3,6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinicacid (406 mg, 1.03 mmole) was combined with3-Oxa-7,9-diaza-bicyclo[3.3.1]nonane-9-carboxylic acid benzyl ester (266mg, 0.9 mmole) which gave7-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-3-oxa-7,9-diaza-bicyclo[3.3.1]nonane-9-carboxylicacid benzyl ester (0.466 g, 0.723 mmol) in 80% yield. MS m/z 639.3(M+H)⁺.

Step 2

Preparation of7-Cyclopentyl-2-[5-(3-oxa-7,9-diaza-bicyclo[3.3.1]nonane-7-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

To a round bottom flask was combined7-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-3-oxa-7,9-diaza-bicyclo[3.3.1]nonane-9-carboxylicacid benzyl ester (0.461 g, 0.722 mmol), methanol ethyl acetate (12 ml),THF (3 ml), methanol (3 ml), and Pd on C/10%. The mixture was put undera balloon of hydrogen and stirred over night. The mixture was purgedwith nitrogen followed by addition of methylene chloride. The resultantmixture was filtered through a pad of celite. The celite was washed withadditional methylene chloride. The organics were combined andconcentrated to a residue. The residue was purified by silica gelchromotography which gave7-Cyclopentyl-2-[5-(3-oxa-7,9-diaza-bicyclo[3.3.1]nonane-7-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide (338 mg, 0.67 mmol) in 93% yield. ¹H NMR (400 MHz,CDCl₃) δ ppm 8.82 (s, 1H), 8.63 (d, J=8.6 Hz, 1H), 8.56 (s, 1H), 8.47(d, J=2.0 Hz, 1H), 7.87 (dd, J1=8.78 Hz, J2=2.26 Hz, 1H), 6.51 (s, 1H),4.83 (m, 1H), 4.47 (s, 1H), 4.09 (m, 4H), 3.77 (s, 1H), 3.45-3.21 (m,4H), 3.19 (s, 6H), 2.59 (m, 2H), 2.11 (m, 5H), 1.77 (m, 2H); HRMS m/z505.2665 (M+H)⁺.

Examples 71-72

Racemic7-Cyclopentyl-2-[5-(3,9-diaza-bicyclo[4.2.1]nonane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide was chirally separated by SFC chromatography,Chiralpak AD-H (Chiral Technologies), 21.2×250 mm, 5 □m, 10% methanol,100 mbar CO₂, 75 g/min flow, Thar SFC Prep-80 system, which gave Example71,7-Cyclopentyl-2-[5-((1S,6R)-3,9-diaza-bicyclo[4.2.1]nonane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide which has a retention time ˜2.5 min and Example 2,7-cyclopentyl-2-[5((1R,6S)-3,9-diaza-bicyclo[4.2.1]nonane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide which has a retention time ˜3.3 min

Example 71

7-Cyclopentyl-2-[5-((1S,6R)-3,9-diaza-bicyclo[4.2.1]nonane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

1H NMR (400 MHz, DMSO-d₆) δ ppm 11.7 (s, 1H), 10.18 (s, 1H), 9.05 (s,1H), 8.52 (s, 1H), 8.13 (d, 1H), 7.8 (d, 1H), 6.85 (s, 1H), 4.8 (m, 2H),4.1 (m. broad, 2H), 3.7 (m. broad, 2H), 3.06 (s, 3H), 3.05 (s, 3H), 2.3(m. broad, 2H), 2.25-1.7 (m. broad, 8H), 1.65 (m. broad, 2H). MS m/z502.7 (M+H)⁺.

Example 72

7-Cyclopentyl-2-[5-((1R,6S)-3,9-diaza-bicyclo[4.2.1]nonane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

1H NMR (400 MHz, DMSO-d₆) δ ppm 11.7 (s, 1H), 10.18 (s, 1H), 9.05 (s,1H), 8.52 (s, 1H), 8.13 (d, 1H), 7.8 (d, 1H), 6.85 (s, 1H), 4.8 (m, 2H),4.1 (m. broad, 2H), 3.7 (m. broad, 2H), 3.06 (s, 3H), 3.05 (s, 3H), 2.3(m. broad, 2H), 2.25-1.7 (m. broad, 8H), 1.65 (m. broad, 2H). MS m/z502.7 (M+H)⁺.

Example 73

7-Cyclopentyl-2-[6-(3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl)-pyridazin-3-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Step 1

Preparation of3-(6-Amino-pyridazine-3-carbonyl)-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester. To a solution of 6-amino-pyridazine-3-carboxylicacid (212 mg, 1.0 mmol) in DMF (5 mL) was added3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (139mg, 1.0 mmol), HATU (456 mg, 1.2 mmol) and N,N-diisopropylethylamine(0.52 mL, 3.0 mmol). The mixture was stirred at room temperatureovernight after which it was diluted with EtOAc, washed with brine,dried over Na₂SO₄, concentrated and purified over normal silica with0-20% MeOH/DCM which gave a white solid (169 mg, 0.51 mmol). MS m/z334.4 (M+H)⁺.

Step 2

Preparation of3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridazine-3-carbonyl]-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester. In a 4 mL microwave vial2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic aciddimethylamide (98 mg, 0.336 mmol),3-(6-amino-pyridazine-3-carbonyl)-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester (112 mg, 0.336 mmol), BINAP (10.5 mg, 0.017 mmol),Cs₂CO₃ (164 mg, 0.504 mmol) and Pd(OAc)₂ (3.8 mg, 0.017 mmol) were addedtogether. The tube was capped and then purged with N₂ three times.Dioxane (1.68 mL) was added and the capped tube was heated to 120° C.for 20 min in a microwave reactor. After cooling the reaction mixturewas diluted with heptane resulting in the crude product precipitatingout. The crude product was isolated by filtration, re-suspended in waterand subjected to vigorous stirring and sonication. After re-isolating byfiltration the product was purified by normal phase silicachromatography with a 0 to 20% MeOH/EtOAc gradient which gave a lighttan solid (115 mg, 0.195 mmol). MS m/z 590.6 (M+H)⁺.

Step 3:

Preparation of7-Cyclopentyl-2-[6-(3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl)-pyridazin-3-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

To a solution of3-[6-(7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridazine-3-carbonyl]-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester (110 mg, 0.187 mmol) in DCM (1 ml) at −78° C. wasadded TFA (1 mL, 13.0 mmol). After warming to room temperature andstirring for 1 h, the reaction was concentrated under reduced pressure.The resulting oily residue was dissolved in 2 mL MeOH, flushed through aPL-HCO3 MP-Resin cartridge to remove TFA, then purified by HPLC whichgave a white solid (55 mg, 0.112 mmol). ¹H NMR (400 MHz, DMSO): δ, 10.71(s, 1H), 8.88 (s, 1H), 8.60 (d, J=8 Hz, 1H), 7.82 (d, J=8 Hz, 1H), 6.68(s, 1H), 4.81-4.72 (m, 1H), 4.22 (d, J=12 Hz, 1H), 3.53 (d, J=12 Hz,1H), 3.48 (br s, 1H), 3.29 (br s, 1H), 3.27 (d, J=12 Hz, 1H), 3.06 (s,3H), 3.05 (s, 3H) 2.93 (d, J=12 Hz, 1H), 2.42-2.33 (m, 2H), 2.01-1.96(m, 4H), 1.72-1.58 (m, 6H); HRMS calcd for C25H31N9O2.H⁺ (M+H)⁺490.2679. found 490.2676 (M+H)⁺.

Example 74

7-Cyclopentyl-2-[5-(8-oxa-3-aza-bicyclo[3.2.1]octane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Preparation of7-Cyclopentyl-2-[5-(8-oxa-3-aza-bicyclo[3.2.1]octane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Following general amide formation method 3,6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinicacid (528 mg, 1.34 mmole) was combined with8-Oxa-3-aza-bicyclo[3.2.1]octane (199 mg, 1.34 mmol) which gave7-Cyclopentyl-2-[5-(8-oxa-3-aza-bicyclo[3.2.1]octane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide (213 mg, 0.435 mmol) in 32.5% yield. ¹H NMR (400 MHz,CDCl₃) δ ppm 1.74 (m, 8H), 2.07 (m, 5H), 2.58 (m, 2H), 3.17 (s, 7H),4.81 (dd, 1H), 6.48 (s, 1H), 7.79 (dd, 8.30 (s, 1H), 8.39 (d, 1H), 8.56(d, 1H), 8.77 (s, 1H) MS m/z 490.5 (M+H)⁺.

Example 75

7-Cyclopentyl-2-[5-(8-oxa-3,10-diaza-bicyclo[4.3.1]decane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Step 1

Preparation of3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-8-oxa-3,10-diaza-bicyclo[4.3.1]decane-10-carboxylicacid tert-butyl ester

Following general amide formation method 3,6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinicacid (385 mg, 0.97 mmole) was combined with8-Oxa-3,10-diaza-bicyclo[4.3.1]decane-10-carboxylic acid tert-butylester (215 mg, 0.887 mmol) which gave3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-8-oxa-3,10-diaza-bicyclo[4.3.1]decane-10-carboxylicacid tert-butyl ester (323 mg, 0.522 mmol) in 59% yield. MS 619.7(M+H)⁺.

Step 2

Preparation of7-Cyclopentyl-2-[5-(8-oxa-3,10-diaza-bicyclo[4.3.1]decane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Following deprotection method 1,3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-8-oxa-3,10-diaza-bicyclo[4.3.1]decane-10-carboxylicacid tert-butyl ester (313 mg, 0.506 mmol) was converted to7-Cyclopentyl-2-[5-(8-oxa-3,10-diaza-bicyclo[4.3.1]decane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide (187 mg, 0.35 mmol) in 69.1% yield. ¹H NMR (400 MHz,CDCl3-d) δ ppm 1.75 (d, 3H) 2.06-2.18 (m, 5H) 2.49-2.66 (m, 2H)3.03-3.14 (m, 2H) 3.18 (s, 6H) 3.42 (dd, 2.0 Hz, 2H) 3.63 (br. s., 1H)3.81 (br. s., 2H) 4.83 (t, 1H) 6.50 (s, 1H) 7.85 (dd, 1H) 8.42 (br. s.,1H) 8.45-8.51 (m, 1H) 8.60 (d, 1H) 8.79 (s, 1H). MS 518.6 (M+H)⁺.

Example 76

7-(1R,2R,4S)-Bicyclo[2.2.1]hept-2-yl-2-[5-(3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Step 1

Racemic7-exo-bicyclo[2.2.1]hept-2-yl-2-chloro-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide was chirally separated by SFC chromatography,Chiralpak AD-H (Chiral Technologies), 21.2×250 mm, 5 μm, 10% methanol,100 mbar CO₂, 75 g/min flow, Thar SFC Prep-80 system, which gaveenantiomer 1:7-(1R,2R,4S)-Bicyclo[2.2.1]hept-2-yl-2-chloro-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide (enantiomer 1 retention time 1.9 min), and enantiomer2:7-(1S,2S,4R)-Bicyclo[2.2.1]hept-2-yl-2-chloro-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide (enantiomer 2 retention time 2.4 min)

Step 2

Preparation of3-[6-((1R,2R,4S)-7-Bicyclo[2.2.1]hept-2-yl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester

Following general N—C coupling procedure 1,17-(1R,2R,4S)-Bicyclo[2.2.1]hept-2-yl-2-chloro-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide (90 mg, 0.28 mmol) with3-(6-Amino-pyridine-3-carbonyl)-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester (99 mg, 0.30 mmol) which gave3-[6-((1R,2R,4S)-7-Bicyclo[2.2.1]hept-2-yl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester and was used as is without furthercharacterization.

Step 3

Preparation of7-(1R,2R,4S)-Bicyclo[2.2.1]hept-2-yl-2-[5-(3,8-diazabicyclo[3.2.1]octane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Following deprotection method 2,3-[6-((1R,2R,4S)-7-Bicyclo[2.2.1]hept-2-yl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester was converted to7-(1R,2R,4S)-Bicyclo[2.2.1]hept-2-yl-2-[5-(3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide (15 mg) in 10% overall yield. ¹H NMR (400 MHz, DMSO-d

) δ 9.94 (s, 1H), 8.82 (s, 1H), 8.39 (s, 1H), 8.29 (d, J=8.6, 1 H), 7.89(d, J=8.6, 1 H), 6.65 (s, 1H), 4.46 (m, 1H), 4.35 (m, 1H), 3.96 (m, 1H),3.04 (s, 6H), 2.86 (m, 3H), 2.62 (m, 3H), 2.37 (m, 1H), 1.85-1.79 (m,5H), 1.55 (m, 2H), 1.22 (m, 3H). MS m/z 515.7 (MH⁺)

Example 77

7-(1S,2S,4R)-Bicyclo[2.2.1]hept-2-yl-2-[5-(3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Step 1

Preparation of3-[6-((1S,2S,4R)-7-Bicyclo[2.2.1]hept-2-yl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester

Following general N—C coupling procedure 1 as in example 76,7-(1S,2S,4R)-Bicyclo[2.2.1]hept-2-yl-2-chloro-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide (90 mg, 0.28 mmol) was combined with3-(6-Amino-pyridine-3-carbonyl)-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester which gave3-[6-((1S,2S,4R)-7-Bicyclo[2.2.1]hept-2-yl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester and was used as is without furthercharacterization.

Step 2

Preparation of7-(1S,2S,4R)-Bicyclo[2.2.1]hept-2-yl-2-[5-(3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Following deprotection method 2,3-[6-((1S,2S,4R)-7-Bicyclo[2.2.1]hept-2-yl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester was converted to7-(1S,2S,4R)-Bicyclo[2.2.1]hept-2-yl-2-[5-(3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide which after purification gave the title compound (5mg) in 3% overall yield. ¹H NMR (400 MHz, DMSO-d

) δ 9.94 (s, 1H), 8.82 (s, 1H), 8.39 (s, 1H), 8.29 (d, J=8.6, 1 H), 7.89(d, J=8.6, 1 H), 6.65 (s, 1H), 4.46 (m, 1H), 4.35 (m, 1H), 3.96 (m, 1H),3.04 (s, 6H), 2.86 (m, 3H), 2.62 (m, 3H), 2.37 (m, 1H), 1.85-1.79 (m,5H), 1.55 (m, 2H), 1.22 (m, 3H).

MS m/z 514.8 (MH⁺)

Example 78

2-[5-(1-Amino-3-aza-bicyclo[3.1.0]hex-3-yl)-pyridin-2-ylamino]-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Step 1

Preparation of[3-(6-Nitro-pyridin-3-yl)-3-aza-bicyclo[3.1.0]hex-1-yl]-carbamic acidtert-butyl ester

Following general N—C coupling procedure 1,5-bromo-2-nitropyridine (50mg, 0.246 mmol), was combined with tert-butyl3-azabicyclo[3.1.0]hexan-1-ylcarbamate (48.8 mg, 0.246 mmol), which gave75 mg of[3-(6-Nitro-pyridin-3-yl)-3-aza-bicyclo[3.1.0]hex-1-yl]-carbamic acidtert-butyl ester in 95% yield. MS (ESI) m/e (M+H⁺): 321.3

Step 2

Preparation of[3-(6-Amino-pyridin-3-yl)-3-aza-bicyclo[3.1.0]hex-1-yl]-carbamic acidtert-butyl ester

To a solution of[3-(6-Nitro-pyridin-3-yl)-3-aza-bicyclo[3.1.0]hex-1-yl]-carbamic acidtert-butyl ester (150 mg, 0.468 mmol) in MeOH—CH2Cl2 (3:1) was addedPd/C (24.92 mg, 0.234 mmol). The resulting mixture was stirred under H2balloon (H2/vacuum exchange three times) at r.t. for 4 h. LCMS showedcomplete conversion. The reaction mixture was then filtered through apad of Celite with DCM and concentrated to give a black precipitate.This precipitate was diluted in ethyl acetate followed by filtration.The filtrate was then evaporated to give 120 mg of[3-(6-Amino-pyridin-3-yl)-3-aza-bicyclo[3.1.0]hex-1-yl]-carbamic acidtert-butyl ester in 88% yield. MS (ESI) m/e (M+H⁺): 291.1

Step 3

Preparation of{3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-3-aza-bicyclo[3.1.0]hex-1-yl}-carbamicacid tert-butyl ester

Following general N—C coupling procedure 1,3-(6-Amino-pyridin-3-yl)-3-aza-bicyclo[3.1.0]hex-1-yl]-carbamic acidtert-butyl ester (120 mg, 0.413 mmol) was combined with2-Chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic aciddimethylamide (121 mg, 0.413 mmol) which gave 200 mg{3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-3-aza-bicyclo[3.1.0]hex-1-yl}-carbamicacid tert-butyl ester in 89% yield. MS (ESI) m/e (M+H⁺): 547.0

Step 4

Preparation of2-[5-(1-Amino-3-aza-bicyclo[3.1.0]hex-3-yl)-pyridin-2-ylamino]-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Following deprotection method 1,{3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-3-aza-bicyclo[3.1.0]hex-1-yl}-carbamicacid tert-butyl ester2-[5-(1-Amino-3-aza-bicyclo[3.1.0]hex-3-yl)-pyridin-2-ylamino]-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide, 20 mg. MS (ESI) m/e (M+H⁺): 447.5; 1H NMR (400 MHz,DMSO-d₆) δ ppm 9.14 (1H, s), 8.72 (1H, s), 8.05 (1H, d), 7.65 (1H, d),7.00 (1H, dd), 6.58 (1H, s), 4.67-4.76 (1H, quin.), 3.62 (1H, d), 3.35(5H, s), 3.22 (1H, d), 3.05 (6H, d), 2.42 (2H, br. s.), 1.96-1.99 (4H,d), 1.63 (2H, br. s.), 0.85 (1H, m), 0.55 (1H, m).

Example 79

7-Cyclopentyl-2-[6-(4-oxo-3,9-diaza-bicyclo[4.2.1]non-3-yl)pyridazin-3-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Step 1

Preparation of2-Amino-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic aciddimethylamide

To a suspension of2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic aciddimethylamide (2.93 g, 10 mmol) in 50 mL Dioxane were added benzophenoneimine (1.90 g, 10.5 mmol), Pd(OAc)₂ (0.11 g, 0.5 mmol), BINAP (0.31 g,0.5 mmol) and Cs₂CO₃ (4.89 g, 15 mmol) and the flask was purged with N₂.Then the tube was sealed and the mixture was heated for 1 h at 120° C.Then the suspension was added with heptane and filtered. The precipitatewas extracted with DCM and the extract was purified by SiO2 columnchromatography to give2-(benzhydrylidene-amino)-7-(1-ethyl-butyl)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide (3.5 g, 8.0 mmol, 80% yield). MS m/z 438.5 (M+H)⁺.

Step 2

Preparation of2-Amino-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic aciddimethylamide

To a solution of2-(benzhydrylidene-amino)-7-(1-ethyl-butyl)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide (3.5 g, 8.0 mmol) in 26.7 mL THF was added aqueous 2MHCl (1.32 mL) and the mixture was stirred for 20 min. To this was added60 mL heptane:EtOAc (4:1 v/v) and 60 mL aqueous 0.5 N HCl and the layerswere separated. The acidic aqueous layer was basified to pH 10 withaqueous 25% NaOH solution and extracted again with EtOAc. The organicextract was then washed with brine, dried (Na₂SO₄), concentrated andpurified via SiO2 column chromatography (0-20% MeOH in EtOAc) to give2-amino-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic aciddimethylamide as a white solid (1.68 g, 6.15 mmol, 77% yield). MS m/z274.4 (M+H)⁺.

Step 3

Synthesis of3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridazin-3-yl]-4-oxo-3,9-diaza-bicyclo[4.2.1]nonane-9-carboxylicacid tert-butyl ester

To a suspension of 3,6-dibromo-pyridazine (400 mg, 1.68 mmol) in 8 mLToluene in a dry pressure tube were added4-oxo-3,9-diaza-bicyclo[4.2.1]nonane-9-carbo-xylic acid tert-butyl ester(323 mg, 1.345 mmol), Pd₂(dba)₃ (154 mg, 0.168 mmol), xantphos (195 mg,0.336 mmol) and NaOt-Bu (242 mg, 2.52 mmol) and the suspension wasbubbled with N² for 3 min. Then the tube was sealed and the mixture washeated for 3 h at 100° C. Then the seal was open and the mixture wasadded with more of Pd₂(dba)₃ (41 mg, 0.045 mmol), xantphos (52 mg, 0.091mmol), NaOt-Bu (65 mg, 0.680 mmol) and2-amino-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic aciddimethylamide (124 mg, 0.453 mmol). The mixture was again heated at 100C for 16 h and the suspension was filtered through a celite plug andwashed with 10% MeOH in DCM. The collective filtrates were combined andpurified by two consecutive SiO₂ columns to give3-[6-(7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)pyridazin-3-yl]-4-oxo-3,9-diaza-bicyclo[4.2.1]nonane-9-carboxylicacid tert-butyl ester (66 mg, 0.112 mmol, 8% yield) as a white solid. MSm/z 590.6 (M+H)⁺.

Step 4

Preparation of Synthesis of7-Cyclopentyl-2-[6-(4-oxo-3,9-diaza-bicyclo[4.2.1]non-3-yl)pyridazin-3-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Following deprotection method 1,3-[6-(7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridazin-3-yl]-4-oxo-3,9-diaza-bicyclo[4.2.1]nonane-9-carboxylicacid tert-butyl ester (60 mg, 0.10 mmol) was converted to7-Cyclopentyl-2-[6-(4-oxo-3,9-diaza-bicyclo[4.2.1]non-3-yl)pyridazin-3-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide (9 mg, 0.018 mmol) in 18% yield. 1H NMR (400 MHz,dichloromethane-d₂) δ ppm 8.69 (s, 1H), 8.63 (d, J=9.6 Hz, 1H), 8.44(br. s., 1H), 7.68 (d, J=9.6 Hz, 1H), 6.39 (s, 1H), 4.72 (m, 1H), 4.36(dd, J=15.2, 6.6 Hz, 1H), 3.88 (d, J=15.2 Hz, 1H), 3.72 (m, 1H), 3.59(m, 1H), 3.02 (s, 6H), 2.87 (m, 1H), 2.75 (m, 1H), 2.42 (m, 2H), 1.98(m, 5H), 1.78 (m, 3H), 1.65 (m, 2H); MS m/z 490.5 (M+H)⁺; HRMS: m/z(M+H) calculated for C₂₅H₃₁N₉O₂: 490.2679. found: 490.2693.

Example 80

7-Cycloheptyl-2-[5-(2-oxo-3,8-diaza-bicyclo[3.2.1]oct-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Step 1

Preparation of3-(6-Nitro-pyridin-3-yl)-2-oxo-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester

Following general N—C coupling procedure 1,5-bromo-2-nitropyridine (110mg, 0.542), was combined with2-Oxo-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester(135 mg, 0.596 mg), which after purification silica gel chromatographygave3-(6-Nitro-pyridin-3-yl)-2-oxo-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester (290 mg, 81%). MS m/z 349.0 (MH⁺), and was useddirectly as is without further characterization.

Step 2

Preparation of3-(6-Amino-pyridin-3-yl)-2-oxo-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester

Following nitro group reduction procedure 1,3-(6-Nitro-pyridin-3-yl)-2-oxo-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester (290 mg, 0.83 mmol) in methanol (10 mL) withnitrogen, then added 10% palladium on charcoal (200 mg, excess). Purgedwith hydrogen and allowed to stir under hydrogen atmosphere for 16hours. Purged with nitrogen and filtered through a pad of celite,washing with methanol. Concentrated in vacuo which gave3-(6-Amino-pyridin-3-yl)-2-oxo-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester (146 mg, 60%). Used without further purification.¹H NMR (400 MHz, DMSO-d6) δ 7.73 (d, J=2.6 Hz, 1H), 7.21 (dd, J=9.1, 2.6Hz 1H), 6.43 (d, J=9.1 Hz, 1H), 6.01 (s, 2H), 4.38 (br. s, 1H), 4.26 (m,1H), 3.77 (m, 1H), 3.30 (m, 1H), 2.17-2.07 (m, 2H), 2.02-1.95 (m, 2H),1.43 (s, 9H); MS m/z 319.5 (MH⁺).

Step 3

Preparation of7-Cycloheptyl-2-[5-(2-oxo-3,8-diaza-bicyclo[3.2.1]oct-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide tert butyl ester

Following general N—C coupling procedure 1,3-(6-Amino-pyridin-3-yl)-2-oxo-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester (146 mg, 0.46 mmol), was combined with2-Chloro-7-cycloheptyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic aciddimethylamide (134 mg, 0.42 mmol), which after workup gave7-Cycloheptyl-2-[5-(2-oxo-3,8-diaza-bicyclo[3.2.1]oct-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide tert butyl ester and was used directly withoutfurther characterization.

Step 4

Preparation of7-Cycloheptyl-2-[5-(2-oxo-3,8-diaza-bicyclo[3.2.1]oct-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Following deprotection method 2,7-cycloheptyl-2-[5-(2-oxo-3,8-diaza-bicyclo[3.2.1]oct-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide tert butyl ester was converted to7-Cycloheptyl-2-[5-(2-oxo-3,8-diaza-bicyclo[3.2.1]oct-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide (100 mg) in 48% yield. MS mh 503.6 (MH⁺); ¹H NMR (400MHz, DMSO-d

) δ 9.78 (s, 1H), 8.81 (s, 1H), 8.46 (d, J=9.1 Hz, 1H), 8.24 (d, J=2.5Hz 1H), 7.70 (dd, J=9.1, 2.5 Hz 1H), 6.63 (s, 1H), 4.44 (m, 1H),3.76-3.70 (m, 2H), 3.62 (m, 1H), 3.16 (s, 1H), 3.08 (s, 3H), 3.06 (s,3H) 2.54 (m, 3H), 2.01-1.75 (m, 8H), 1.74-1.58 (m, 4H), 1.5-1.43 (m,2H).

Example 81

7-Cycloheptyl-2-[5-(1-oxo-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Step 1

Preparation of Cis-tert-butyl5-(6-nitropyridin-3-yl)-4-oxohexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate

Following general N—C coupling procedure 1,5-bromo-2-nitropyridine (4.71g, 23.2 mmol, 1.05 eq) was combined with cis-tert-butyl4-oxohexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (5 g, 22.1 mmol,1.0 eq), which after silica gel purification gave cis-tert-butyl5-(6-nitropyridin-3-yl)-4-oxohexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate(6.3 g) in 81% yield. ¹H NMR (400 MHz, CDCl₃) δ ppm 8.75 (m, 2H), 8.34(d, J=9.09 Hz, 1H), 4.20 (dd, J1=9.85 Hz, J2=6.82 Hz, 1H), 4.02-3.85 (m,2H), 3.80 (d, J=10.11 Hz, 1H), 3.68 (m, 1H), 1.52-1.43 (m, 3H).

Step 2

Preparation of cis-tert-butyl5-(6-aminopyridin-3-yl)-4-oxohexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate

Following nitro group reduction procedure 1, cis-tert-butyl5-(6-nitropyridin-3-yl)-4-oxohexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate(1.05 g, 3.01 mmol.) was reduced to cis-tert-butyl5-(6-aminopyridin-3-yl)-4-oxohexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate(1.0 g) in quantitative yield. ¹H NMR (400 MHz, CDCl₃) δ ppm 8.09 (s,1H), 7.95 (br s, 1H), 6.57 (d, J=9.6 Hz, 1H), 4.58 (br s, 2H), 4.04 (dd,J1=10.11 Hz, J2=6.57 Hz, 1H). 3.93 (dd, J1=11.62 Hz, J2=2.02 Hz, 1H)3.86 (t, 1H), 3.69-3.55 (m, 2H), 3.24 (m, 2H), 3.11 (m, 1H), 1.48 (s,9H); MS m/z 319.4 (M+H)⁺.

Step 3

Preparation of cis-tert-butyl5-(6-(7-cycloheptyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)pyridin-3-yl)-4-oxohexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate

Following general N—C coupling procedure 1,2-chloro-7-cycloheptyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide(50.4 mg, 0.157 mmol) was combined with cis-tert-butyl5-(6-aminopyridin-3-yl)-4-oxohexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate(50 mg, 0.157 mmol, 1.0 eq), gave after silica gel chromatography,cis-tert-butyl5-(6-(7-cycloheptyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)pyridin-3-yl)-4-oxohexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate(90 mg) in 94% yield. ¹H NMR (400 MHz, CDCl₃) δ ppm 8.76 (s, 1H), 8.65(d, J=9.6 Hz, 1H), 8.54 (s, 1H), 8.34 (s, 1H), 8.18 (s, 1H), 6.46 (s,1H), 4.54 (m, 1H), 4.13 (dd, J1=9.85 Hz, J2=6.82 Hz, 1H), 3.97 (d,J=10.61 Hz, 1H), 3.89 (t, J=9.85 Hz, 1H), 3.62-3.76 (m, 2H), 3.06-3.40(m, 9H), 2.65 (q, J=10.95 Hz, 2H), 2.02 (m, 2H), 1.89 (m, 2H), 1.74 (m,4H), 1.60 (m, 2H), 1.49 (m, 9H). MS m/z 603.6 (M+H)⁺.

Step 4

Preparation of7-cycloheptyl-N,N-dimethyl-2-(5-(cis-1-oxohexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

Following deprotection method 2,7-Cycloheptyl-N,N-dimethyl-2-(5-(cis-1-oxohexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamidewas obtained after purification (64 mg) in 85% yield. ¹H NMR (400 MHz,CDCl₃) δ ppm 8.73 (s, 1H), 8.62 (d, J=9.6 Hz, 1H), 8.42 (d, J=2.53 Hz,1H), 8.26 (dd, J1=9.09, J2=3.03 Hz, 1H), 8.01 (s, 1H), 7.28 (s, 1H),6.45 (s, 1H), 4.54 (m, 1H), 4.17 (m, 1H), 3.63 (dd, J1=9.60, J2=3.03 Hz,1H), 3.53 (m, 1H), 3.31-3.12 (m, 8H), 3.11-2.92 (m, 2H), 2.64 (m, 2H),2.02 (m, 2H), 1.88 (m, 2H), 1.81-1.67 (m, 5H), 1.59 (m, 2H); HRMS m/z503.2889 (M+H)⁺.

Step 5

7-Cycloheptyl-N,N-dimethyl-2-(5-(cis-1-oxohexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide(56 mg), a cis racemic compound was separated by CHIRALPAK® AS-H chiralcolumn. The separetion Mobil phase was 30% MeOH with 0.2% DEA. Two peakswere collected. The faster moving enantiomer was collected asenantiomer-1 (23 mg, 38% yield) and the slower moving enantiomer asenantiomer-2 (25 mg, 43% yield).

Example 82

7-cycloheptyl-N,N-dimethyl-2-(5-((3aS,6aR)-1-oxohexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide.Enantiomer-1

¹H NMR (400 MHz, CDCl₃) δ ppm 8.73 (s, 1H), 8.62 (d, J=9.09 Hz, 1H),8.42 (d, J=2.53 Hz, 1H), 8.26 (dd, J1=9.35, J2=2.78 Hz, 1H), 8.02 (s,1H), 7.28 (s, 1H), 6.45 (s, 1H), 4.54 (m, 1H), 4.17 (m, 1H), 3.63 (dd,J1=9.85, J2=2.78 Hz, 1H), 3.53 (m, 1H), 3.31-3.12 (m, 8H), 3.11-2.94 (m,2H), 2.64 (m, 2H), 2.02 (m, 2H), 1.88 (m, 2H), 1.81-1.67 (m, 5H), 1.59(m, 2H); HRMS m/z 503.2882 (M+H)⁺.

Example 83

7-cycloheptyl-N,N-dimethyl-2-(5-((3aR,6aS)-1-oxohexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide.Enantiomer-2

¹H NMR (400 MHz, CDCl₃) δ ppm 8.73 (s, 1H), 8.62 (d, J=9.09 Hz, 1H),8.42 (d, J=2.53 Hz, 1H), 8.26 (dd, J1=8.84, J2=2.78 Hz, 1H), 8.00 (s,1H), 7.28 (s, 1H), 6.45 (s, 1H), 4.54 (m, 1H), 4.17 (m, 1H), 3.63 (dd,J1=9.85, J2=2.78 Hz, 1H), 3.53 (m, 1H), 3.31-3.12 (m, 8H), 3.11-2.94 (m,2H), 2.64 (m, 2H), 2.02 (m, 2H), 1.88 (m, 2H), 1.81-1.67 (m, 5H), 1.59(m, 2H); HRMS m/z 503.2890 (M+H)⁺.

Example 84

7-cyclopentyl-N,N-dimethyl-2-(5-cis-1-oxohexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

Step 1

7-cyclopentyl-N,N-dimethyl-2-(5-cis-1-oxohexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

Following general N—C coupling procedure 1,2-chloro-7-cyclopentyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamideand cis-tert-butyl5-(6-aminopyridin-3-yl)-4-oxohexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylatewere combined to give after purification cis-tert-butyl5-(6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)pyridin-3-yl-4-oxohexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylatecarboxylate (82 mg) in 89% yield. ¹H NMR (400 MHz, CDCl₃) δ ppm 8.74 (s,1H), 8.52 (d, J=9.09 Hz, 1H), 8.40 (s, 1H), 8.17 (br s, 1H), 8.08 (s,1H), 6.46 (s, 1H), 4.81 (m, 1H), 4.11 (dd, J1=10.11 Hz, J2=6.57 Hz, 1H),3.96 (d, J=11.62 Hz, 1H), 3.88 (t, J=9.60 Hz, 1H), 3.67 (m, 2H), 3.28(m, 2H), 3.14 (m, 7H), 2.58 (m, 2H), 2.08 (m, 4H), 1.74 (m, 2H), 1.48(m, 9H). LCMS m/z 575.6 (M+H)⁺.

Step 2

Following deprotection method 2,7-cyclopentyl-N,N-dimethyl-2-(5-cis-1-oxohexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide(61 mg) was obtained in 90% yield. ¹H NMR (400 MHz, CDCl₃) δ ppm 8.75(s, 1H), 8.51 (d, J=9.09 Hz, 1H), 8.44 (d, J=2.53 Hz, 1H), 8.23 (dd,J1=9.09, J2=2.53 Hz, 1H), 8.13 (s, 1H), 6.47 (s, 1H), 4.82 (m, 1H), 4.16(m, 1H), 3.62 (dd, J1=10.11, J2=3.03 Hz, 1H), 3.53 (dd, J1=11.12,J2=2.02 Hz, 1H), 3.29-3.13 (m, 8H), 3.08-2.98 (m, 2H), 2.59 (m, 2H),2.08 (m, 5H), 1.75 (m, 2H)

HRMS m/z 475.2591 (M+H)⁺.

Step 3

7-cyclopentyl-N,N-dimethyl-2-(5-cis-1-oxohexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide(52 mg), was separated by CHIRALPAK® AS-H chiral column. The separationMobil phase was 35% MeOH with 0.2% DEA. Two peaks were collected. Thefaster moving enantiomer was collected as enantiomer-1 (15 mg, 29%yield) and the slower moving enantiomer as enantiomer-2 (18 mg, 34%yield).

Example 85

7-cyclopentyl-N,N-dimethyl-2-(5-((3aS,6aR)-1-oxohexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide.Enantiomer-1

¹H NMR (400 MHz, CDCl₃) δ ppm 8.75 (s, 1H), 8.51 (d, J=9.09 Hz, 1H),8.44 (d, J=2.53 Hz, 1H), 8.23 (dd, J=9.09, 3.03 Hz, 1H), 8.06 (s, 1H),6.47 (s, 1H), 4.82 (m, 1H), 4.17 (m, 1H), 3.64 (dd, J1=9.85, J2=2.78 Hz,1H), 3.55 (d, J=11.12, 1 H), 3.29-3.13 (m, 8H), 3.08-2.98 (m, 2H), 2.59(m, 2H), 2.09 (m, 5H), 1.75 (m, 2H)

HRMS m/z 475.2568 (M+H)⁺.

Example 86

7-cyclopentyl-N,N-dimethyl-2-(5-((3aR,6aS)-1-oxohexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide.Enantiomer-2

¹H NMR (400 MHz, CDCl₃) δ ppm 8.74 (s, 1H), 8.51 (d, J=9.09 Hz, 1H),8.42 (d, J=2.53 Hz, 1H), 8.24 (dd, J1=9.09, J2=2.53 Hz, 1H), 8.01 (s,1H), 6.47 (s, 1H), 4.82 (m, 1H), 4.17 (m, 1H), 3.62 (dd, J=9.85, 2.78Hz, 1H), 3.53 (d, J=11.62, 1 H), 3.29-3.13 (m, 8H), 3.08-2.98 (m, 2H),2.59 (m, 2H), 2.09 (m, 5H), 1.75 (m, 2H)

HRMS m/z 475.2573 (M+H)⁺.

Example 87

cis-tert-butyl5-(6-(7-cycloheptyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)pyridin-3-yl)-6-oxohexahydro-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate

Step 1

Cis-tert-butyl5-(6-nitropyridin-3-yl)-6-oxohexahydro-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate

Following general N—C coupling procedure 1,5-bromo-2-nitropyridine andcis-tert-butyl6-oxohexahydro-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate were combinedand gave after purification cis-tert-butyl5-(6-nitropyridin-3-yl)-6-oxohexahydro-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate(1.0 g) in 85% yield. ¹H NMR (400 MHz, CDCl₃) δ ppm 8.58 (d, J=2.53 Hz,1H), 8.28 (d, J=8.59 Hz, 1H), 8.07 (dd, J1=8.84, J2=2.27 Hz, 1H),4.18-3.61 (m, 4H), 3.29 (m, 2H), 2.85 (m, 3H), 2.55 (m, 1H), 1.47 (s,9H)

LCMS m/z 362.8 (M+H)⁺.

Step 2

Preparation of cis-tert-butyl5-(6-aminopyridin-3-yl)-6-oxohexahydro-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate

Following nitro group reduction procedure 1, cis-tert-butyl5-(6-aminopyridin-3-yl)-6-oxohexahydro-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylatewas obtained (300 mg) in 96% yield. ¹H NMR (400 MHz, CDCl₃) δ ppm 7.93(d, J=2.02 Hz, 1H), 7.45 (dd, J1=9.09, J2=2.53 Hz, 1H), 6.59 (d, J=9.09Hz, 1H), 4.92 (br s, 2H), 3.83-3.00 (m, 6H), 2.91-2.66 (m, 3H), 2.48(dd, J1=16.42, J2=5.81 Hz, 1H). LCMS m/z 332.8 (M+H)⁺.

Step 3

Preparation of7-cycloheptyl-N,N-dimethyl-2-(5-(cis-6-oxotetrahydro-1H-pyrrolo[3,4-c]pyridin-5(6H,7H,7aH)-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

Following general N—C coupling procedure 1,2-chloro-7-cycloheptyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamideand cis-tert-butyl5-(6-aminopyridin-3-yl)-6-oxohexahydro-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylatewere combined and gave after purification cis-tert-butyl5-(6-(7-cycloheptyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)pyridin-3-yl)-6-oxohexahydro-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate(85 mg) in 86% yield. ¹H NMR (400 MHz, CDCl₃) δ ppm 8.77 (s, 1H), 8.66(d, J=9.09 Hz, 1H), 8.48 (br s, 1H), 8.24 (s, 1H), 7.64 (dd, J1=9.09 Hz,J2=2.53 Hz, 1H), 6.45 (s, 1H), 4.53 (m, 1H), 3.84 (dd, J1=13.14 Hz,J2=5.56 Hz, 1H), 3.70 (m, 3H), 3.31 (m, 2H), 3.17 (s, 6H), 2.82 (m, 3H),2.63 (m, 2H), 2.51 (dd, J1=16.42 Hz, J2=5.81 Hz, 1H), 2.01 (m, 2H), 1.87(m, 2H), 1.73 (m, 4H), 1.58 (m, 2H), 1.48 (s, 9H). LCMS m/z 617.7(M+H)⁺.

Step 4

Preparation of7-cycloheptyl-N,N-dimethyl-2-(5-(cis-6-oxotetrahydro-1H-pyrrolo[3,4-c]pyridin-5(6H,7H,7aH)-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

Following deprotection method 2,7-cycloheptyl-N,N-dimethyl-2-(5-(cis-6-oxotetrahydro-1H-pyrrolo[3,4-c]pyridin-5(6H,7H, 7aH)-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide(64 mg) was obtained in 89% yield. ¹H NMR (400 MHz, CDCl₃) δ ppm 8.74(s, 1H), 8.64 (d, J=9.09 Hz, 1H), 8.24 (d, J=2.53 Hz, 1H), 8.19 (s, 1H),7.68 (dd, J1=8.84, J2=2.78 Hz, 1H), 6.46 (s, 1H), 4.54 (m, 1H), 3.88(dd, J1=13.14, J2=4.04 Hz, 1H), 3.63 (dd, J1=13.14, J2=5.05 Hz, 1H),3.29 (m, 2H), 3.18 (s, 6H), 2.84-2.50 (m, 7H), 2.02 (m, 2H), 1.93-1.66(m, 7H), 1.58 (m, 2H). HRMS m/z 517.3062 (M+H)⁺.

Step 5

7-Cycloheptyl-N,N-dimethyl-2-(5-(cis-6-oxotetrahydro-1H-pyrrolo[3,4-c]pyridin-5(6H,7H,7aH)-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide(56 mg), a cis racemic compound was separated by CHIRALPAK® AD-H chiralcolumn. The separetion Mobil phase was 35% MeOH with 0.2% DEA. Two peakswere collected. The faster moving enantiomer was collected asenantiomer-1 (16 mg, 28% yield) and the slower moving enantiomer asenantiomer-2 (16 mg, 28% yield). The absolute stereo configurations werenot determined.

Example 88

7-cycloheptyl-N,N-dimethyl-2-(5-(cis-6-oxotetrahydro-1H-pyrrolo[3,4-c]pyridin-5(6H,7H, 7aH)-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide.Enantiomer-1

¹H NMR (400 MHz, CDCl₃) δ ppm 8.78 (s, 1H), 8.66 (d, J=9.09 Hz, 1H),8.46 (s, 1H), 8.29 (d, J=2.02 Hz, 1H), 8.19 (s, 1H), 7.68 (dd, J1=8.84,J2=2.78 Hz, 1H), 6.46 (s, 1H), 4.54 (m, 1H), 3.90 (dd, J1=12.63, J2=4.04Hz, 1H), 3.71 (dd, J1=13.14, J2=4.55 Hz, 1H), 3.37 (m, 2H), 3.19 (s,6H), 2.94-2.57 (m, 7H), 2.02 (m, 2H), 1.96-1.65 (m, 7H), 1.58 (m, 2H).HRMS m/z 517.3051 (M+H)⁺.

Example 89

7-cycloheptyl-N,N-dimethyl-2-(5-(cis-6-oxotetrahydro-1H-pyrrolo[3,4-c]pyridin-5(6H,7H,7aH)-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide.Enantiomer-2. ¹H NMR (400 MHz, CDCl₃) δ ppm 8.75 (s, 1H), 8.63 (d,J=9.09 Hz, 1H), 8.35 (s, 1H), 8.25 (d, J=2.53 Hz, 1H), 7.66 (dd,J1=9.09, J2=2.53 Hz, 1H), 6.44 (s, 1H), 4.53 (m, 1H), 3.87 (dd,J1=13.39, J2=4.29 Hz, 1H), 3.64 (dd, J1=13.14, J2=5.56 Hz, 1H), 3.30 (m,2H), 3.17 (s, 6H), 2.87-2.50 (m, 7H), 2.04 (m, 2H), 1.86 (m, 2H), 1.73(m, 3H), 1.58 (m, 2H). HRMS m/z 517.3044 (M+H)⁺.

Example 90

Step 1

7-cyclopentyl-N,N-dimethyl-2-(5-(cis-6-oxotetrahydro-1H-pyrrolo[3,4-c]pyridin-5(6H,7H,7aH)-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

Following general N—C coupling procedure 1,2-chloro-7-cyclopentyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamideand cis-tert-butyl5-(6-aminopyridin-3-yl)-6-oxohexahydro-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylatewere combined and gave after purification cis-tert-butyl5-(6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)pyridin-3-yl)-6-oxohexahydro-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate(81 mg) in 86% yield. ¹H NMR (400 MHz, CDCl₃) δ ppm 8.79 (s, 1H), 8.56(s, 1H), 8.53 (s, 1H), 8.24 (d, J=2.53 Hz, 1H), 7.63 (dd, J1=9.09 Hz,J2=2.53 Hz, 1H), 6.46 (s, 1H), 4.81 (m, 1H), 3.84 (dd, J1=13.14 Hz,J2=5.56 Hz, 1H), 3.78-3.63 (m, 3H), 3.49-3.21 (m, 2H), 3.16 (s, 6H),2.79 (m, 3H), 2.55 (m, 3H), 2.07 (m, 4H), 1.72 (m, 2H), 1.48 (s, 9H).LCMS m/z 589.6 (M+H)⁺.

Step 2

Following deprotection method 2,7-cyclopentyl-N,N-dimethyl-2-(5-(cis-6-oxotetrahydro-1H-pyrrolo[3,4-c]pyridin-5(6H,7H,H)-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (64mg) was obtained in 86% yield. ¹H NMR (400 MHz, CDCl₃) δ ppm 8.74 (s,1H), 8.52 (d, J=8.59 Hz, 1H), 8.22 (d, J=2.53 Hz, 1H), 8.09 (s, 1H),7.66 (dd, J1=8.84 Hz, 0.12=2.78 Hz, 1H), 6.46 (s, 1H), 4.81 (m, 1H),3.87 (dd, J1=12.88 Hz, J2=4.29 Hz, 1H), 3.63 (dd, J1=12.88 Hz, J2=5.31Hz, 1H), 3.30 (m, 2H), 3.17 (m, 6H), 2.87-2.49 (m, 7H), 2.07 (m, 5H),1.73 (m, 2H); HRMS m/z 489.2727 (M+H)⁺.

Step 3

7-Cyclopentyl-N,N-dimethyl-2-(5-(cis-6-oxotetrahydro-1H-pyrrolo[3,4-c]pyridin-5(6H,7H,7aH)-yl)pyridin-2-yl amino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide(56 mg), a cis racemic compound was chirally separated by CHIRALPAK®AD-H chiral column. The separetion Mobil phase was 40% IPA with 0.2%DEA. Two peaks were collected. The faster moving enantiomer wascollected as enantiomer-1 (16 mg, 28% yield) and the slower movingenantiomer was as enantiomer-2 (17 mg, 30% yield). The absolute stereoconfigurations were not determined.

Example 91

7-cyclopentyl-N,N-dimethyl-2-(5-(cis-6-oxotetrahydro-1H-pyrrolo[3,4-c]pyridin-5(6H,7H,7aH)-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

¹H NMR (400 MHz, CDCl₃) δ ppm 8.76 (s, 1H), 8.53 (d, J=9.09 Hz, 1H),8.27 (m, 2H), 7.66 (dd, J1=9.09 Hz, J2=2.53 Hz, 1H), 6.47 (s, 1H), 4.81(m, 1H), 3.88 (d, J=13.64 Hz, 1H), 3.66 (dd, J1=13.14 Hz, J2=5.05 Hz,1H), 3.34 (m, 2H), 3.17 (m, 6H), 2.91-2.53 (m, 7H), 2.07 (m, 5H), 1.73(m, 2H); HRMS m/z 489.2726 (M+H)⁺.

Example 92

7-cyclopentyl-N,N-dimethyl-2-(5-(cis-6-oxotetrahydro-1H-pyrrolo[3,4-c]pyridin-5(6H,7H,7aH)-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

¹H NMR (400 MHz, CDCl₃) δ ppm 8.75 (s, 1H), 8.52 (d, J=9.09 Hz, 1H),8.24 (m, 2H), 7.66 (dd, J1=9.09 Hz, J2=2.53 Hz, 1H), 6.46 (s, 1H), 4.81(m, 1H), 3.88 (dd, J1=13.14 Hz, J2=4.55 Hz, 1H), 3.65 (dd, J1=13.39 Hz,J2=4.80 Hz, 1H), 3.32 (m, 2H), 3.17 (m, 6H), 2.89-2.52 (m, 7H), 2.07 (m,5H), 1.74 (m, 2H); HRMS m/z 489.2726 (M+H)⁺.

Example 93

Preparation of7-cycloheptyl-N,N-dimethyl-2-(5-((3aS,7aR)-2-methyl-6-oxotetrahydro-1H-pyrrolo[3,4-c]pyridin-5(6H,7H,7aH)-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

To a solution of7-cycloheptyl-N,N-dimethyl-2-(5-((3aS,7aR)-6-oxotetrahydro-1H-pyrrolo[3,4-c]pyridin-5(6H,7H,7aH)-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide(from example 89, enantiomer-2) (66 mg, 0.128 mmol, 1 eq) in THF (2.0mL) was added 37% aquous solution of formaldehyde (0.048 mL, 0.639 mmol,5 eq). The reaction mixture was stirred at room temperature for 5minutes. Solid sodium triacetoxyhydroborate (81 mg, 0.383 mmol, 3 eq wasadded into the mixture. The reaction was stirred for 10 more minutes andquenched with a drop of TEA and naturalized with amonia in methanol. Theresidue was concentrated under vacuum and purified by columnchromatography (NH3/MeOH/CH₂Cl₂) to provide7-cycloheptyl-N,N-dimethyl-2-(5-((3aS,7aR)-2-methyl-6-oxotetrahydro-1H-pyrrolo[3,4-c]pyridin-5(6H,7H,7aH)-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide(67 mg) in quantitative yield. ¹H NMR (400 MHz, CDCl₃) δ ppm 8.74 (s,1H), 8.63 (d, J=9.09 Hz, 1H), 8.27 (s, 1H), 8.24 (d, J=2.53 Hz, 1H),7.67 (dd, J1=9.09, J2=2.53 Hz, 1H), 6.44 (s, 1H), 4.73 (s, 3H), 4.52 (m,1H), 3.83 (dd, J1=13.14, J2=4.04 Hz, 1H), 3.65 (dd, J1=13.14, J2=4.04Hz, 1H), 3.17 (s, 6H), 2.91-2.51 (m, 7H), 2.36 (m, 4H), 2.01 (m, 2H),1.87 (m, 2H), 1.79-1.51 (m, 5H); HRMS m/z 531.3219 (M+H)⁺.

Example 94

7-cyclohexyl-N,N-dimethyl-2-(5-((1R,3r,5S)-2′-oxo-8-azaspiro[bicyclo[3.2.1]octane-3,5′-oxazolidine]-3′-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide.

Step 1

Preparation of (1R,3r,5S)-tert-butyl3′-(6-(7-cyclohexyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)pyridin-3-yl)-2′-oxo-8-azaspiro[bicyclo[3.2.1]octane-3,5′-oxazolidine]-8-carboxylate

Following general N—C coupling procedure 1,(1R,3r,5S)-3′-(6-aminopyridin-3-yl)-8-azaspiro[bicyclo[3.2.1]octane-3,5′-oxazolidin]-2′-one(0.350 g, 0.935 mmol, 1.0 eq) was combined with2-Chloro-7-cyclohexyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic aciddimethylamide (0.287 g, 0.935 mmol, 1.0 eq) which gave(1R,3r,5S)-tert-butyl3′-(6-(7-cyclohexyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)pyridin-3-yl)-2′-oxo-8-azaspiro[bicyclo[3.2.1]octane-3,5′-oxazolidine]-8-carboxylate(0.454 g) in 75% yield. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.26-1.45(m, 3H) 1.49 (s, 9H) 1.81 (d, J=11.62 Hz, 1H) 1.87-2.05 (m, 7H)2.05-2.22 (m, 4H) 2.22-2.32 (m, 2H) 2.52-2.73 (m, 2H) 3.16 (s, 6H) 3.72(s, 2H) 4.22-4.47 (m, 3H) 6.44 (s, 1H) 8.06 (dd, J=9.35, 2.78 Hz, 1H)8.32 (d, J=2.53 Hz, 1H) 8.43 (s, 1H) 8.60 (d, J=9.09 Hz, 1H) 8.76 (s,1H). MS m/z 645.7 (M+H)⁺

Step 2:

Preparation of7-cyclohexyl-N,N-dimethyl-2-(5-((1R,3r,5S)-2′-oxo-8-azaspiro[bicyclo[3.2.1]octane-3,5′-oxazolidine]-3′-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

Following deprotection method 1, (1R,3r,5S)-tert-butyl3′-(6-(7-cyclohexyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)pyridin-3-yl)-2′-oxo-8-azaspiro[bicyclo[3.2.1]octane-3,5′-oxazolidine]-8-carboxylate(0.450 g, 0.713 mmol) was converted to7-cyclohexyl-N,N-dimethyl-2-(5-((1R,3r,5S)-2′-oxo-8-azaspiro[bicyclo[3.2.1]octane-3,5′-oxazolidine]-3′-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide(0.286 g, 0.517 mmol) in 73% yield. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm1.28-1.51 (m, 3H) 1.62 (br. s., 1H) 1.71-1.87 (m, 3H) 1.87-1.99 (m, 5H)2.01 (d, J=3.01 Hz, 1H) 2.20 (d, J=14.05 Hz, 2H) 2.25-2.37 (m, 2H)2.52-2.71 (m, 2H) 3.16 (s, 6H) 3.65 (br. s., 2H) 3.71 (s, 2H) 4.27-4.43(m, 1H) 6.44 (s, 1H) 7.91 (s, 1H) 8.10 (dd, J=9.29, 2.76 Hz, 1H) 8.22(d, J=2.51 Hz, 1H) 8.58 (d, J=9.03 Hz, 1H) 8.70 (s, 1H); HRMS calc form/z=545.2994 and found m/z=545.2989 (M+H)

Example 95

Preparation of7-cyclopentyl-N,N-dimethyl-2-(5-((3aR,6aS)-5-methyl-1-oxohexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

Following general reductive alkylation method1,7-cyclopentyl-N,N-dimethyl-2-(5-((3as,6ar)-5-methyl-1-oxohexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamidewas prepared.

Example 96

Step 1

4-(6-nitropyridin-3-yl)-1,4-diazabicyclo[3.2.2]nonan-3-one

Following general N—C coupling procedure 1,5-bromo-2-nitropyridine and1,4-diazabicyclo[3.2.2]nonan-3-one were combined and gave4-(6-nitropyridin-3-yl)-1,4-diazabicyclo[3.2.2]nonan-3-one (418 mg) in64% yield.

¹H NMR (400 MHz, CDCl₃) δ ppm 8.53 (d, J=2.53 Hz, 1H), 8.30 (d, J=8.59Hz, 1H), 7.94 (dd, J1=8.59, J2=2.53 Hz, 1H), 4.00-3.93 (m, 3H), 3.19 (m,4H), 2.38 (m, 2H), 2.13 (m, 2H); LCMS m/z 263.4 (M+H)⁺.

Step 2

4-(6-aminopyridin-3-yl)-1,4-diazabicyclo[3.2.2]nonan-3-one

Following nitro group reduction procedure 1,4-(6-aminopyridin-3-yl)-1,4-diazabicyclo[3.2.2]nonan-3-one, (322 mg) wasobtained in 88% yield.

¹H NMR (400 MHz, DMSO-d6) δ ppm 7.73 (d, J=2.53 Hz, 1H), 7.22 (dd,J1=8.84, J2=2.78 Hz, 1H), 6.44 (d, J=8.59 Hz, 1H), 5.98 (br s, 2H), 3.73(s, 2H), 3.62 (m, 1H), 3.05 (d, J=7.33 Hz, 4H) 2.25 (m, 2H), 1.94 (m,2H)

LCMS m/z 233.4 (M+H)⁺.

Step 3

7-cyclopentyl-N,N-dimethyl-2-(5-(3-oxo-1,4-diazabicyclo[3.2.2]nonan-4-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

Following general N—C coupling procedure 1,4-(6-aminopyridin-3-yl)-1,4-diazabicyclo[3.2.2]nonan-3-one was combinedwith2-chloro-7-cyclopentyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamideand gave7-cyclopentyl-N,N-dimethyl-2-(5-(3-oxo-1,4-diazabicyclo[3.2.2]nonan-4-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide,99 mg in 86% yield. ¹H NMR (400 MHz, CDCl₃) δ ppm 8.74 (s, 1H), 8.55 (d,J=9.09 Hz, 1H), 8.16 (d, J=2.02 Hz, 1H), 8.09 (s, 1H), 7.55 (dd, J1=9.09Hz, J2=2.53 Hz, 1H), 6.47 (s, 1H), 4.81 (m, 1H), 3.93 (s, 2H), 3.82 (m,1H), 3.19 (m, 10H), 2.59 (m, 2H), 2.41 (m, 2H), 2.07 (m, 6H), 1.74 (m,2H); HRMS m/z 489.2740 (M+H)⁺.

Example 97

7-cycloheptyl-N,N-dimethyl-2-(5-(3-oxo-1,4-diazabicyclo[3.2.2]nonan-4-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

Following general N—C coupling procedure 1,2-chloro-7-cycloheptyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamidewas combined with4-(6-aminopyridin-3-yl)-1,4-diazabicyclo[3.2.2]nonan-3-one and gave7-cycloheptyl-N,N-dimethyl-2-(5-(3-oxo-1,4-diazabicyclo[3.2.2]nonan-4-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide(103 mg) in 77% yield. ¹H NMR (400 MHz, CDCl₃) δ ppm 8.73 (s, 1H), 8.66(d, J=9.09 Hz, 1H), 8.17 (d, J=2.02 Hz, 1H), 8.14 (s, 1H), 7.55 (dd,J1=9.09 Hz, J2=2.53 Hz, 1H), 6.45 (s, 1H), 4.53 (m, 1H), 3.95 (s, 2H),3.83 (m, 1H), 3.21 (m, 10H), 2.64 (m, 2H), 2.42 (m, 2H), 2.14-1.54 (m,12H); HRMS m/z 517.3049 (M+H)⁺.

Example 98

7-Cyclohexyl-2-[5-(1-oxo-hexahydro-pyrrolo[1,2-a]pyrazin-2-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Step 1:

Preparation of2-(6-Nitro-pyridin-3-yl)-hexahydro-pyrrolo[1,2-a]pyrazin-1-one

Following general N—C coupling procedure 1,hexahydro-pyrrolo[1,2-a]pyrazin-1-one (0.202 g, 1.44 mmol), was combinedwith 5-bromo-2-nitropyridine (0.293 g, 1.44 mmol, 1.0 eq) which gave2-(6-Nitro-pyridin-3-yl)hexahydro-pyrrolo[1,2-a]pyrazin-1-one as a tansolid (0.170 g, 0.616 mmol) in 43% yield. ¹H NMR (400 MHz, CDCl₃) δ ppm1.79-2.19 (m, 1H) 2.31 (br. s., 1H) 2.77 (br. s., 1H) 2.98-3.16 (m, 1H)3.26 (dt, J=12.05, 4.52 Hz, 1H) 3.47 (br. s., 1H) 3.80 (br. s., 1H)3.95-4.23 (m, 1H) 8.15 (dd, J=8.53, 2.51 Hz, 1H) 8.32 (d, J=8.53 Hz, 1H)8.70 (d, J=2.51 Hz, 1H). MS m/z 263.1 (M+H)⁺.

Step 2:

2-(6-Amino-pyridin-3-yl)-hexahydro-pyrrolo[1,2-a]pyrazin-1-one

Following nitro group reduction procedure 1,2-(6-Nitro-pyridin-3-yl)-hexahydro-pyrrolo[1,2-a]pyrazin-1-one (0.170 g,0.648 mmol) was converted to2-(6-Amino-pyridin-3-yl)-hexahydro-pyrrolo[1,2-a]pyrazin-1-one andisolated as a yellow solid (0.126 g, 0.542) in 84% yield. ¹H NMR (400MHz, MeOD) δ ppm 1.78-2.11 (m, 1H) 2.16-2.35 (m, 1H) 2.80 (ddd, J=10.04,8.03, 6.02 Hz, 1H) 2.97-3.11 (m, 1H) 3.11-3.25 (m, 1H) 3.42-3.52 (m, 1H)3.59 (ddd, J=12.42, 4.39, 4.27 Hz, 1H) 3.85 (ddd, J=12.55, 8.53, 4.52Hz, 1H) 6.60 (d, J=8.03 Hz, 1H) 7.39 (dd, J=9.03, 2.51 Hz, 1H) 7.83 (d,J=2.01 Hz, 1H)

MS m/z 233.2 (M+H)⁺.

Step 3:

7-Cyclohexyl-2-[5-(1-oxo-hexahydro-pyrrolo[1,2-a]pyrazin-2-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Following general N—C coupling procedure 1,2-(6-amino-pyridin-3-yl)-hexahydro-pyrrolo[1,2-a]pyrazin-1-one (0.050 g,0.215 mmol) was combined with2-chloro-7-cyclohexyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic aciddimethylamide (0.066 g, 0.215 mmol, 1.0 eq), and gave7-Cyclohexyl-2-[5-(1-oxo-hexahydro-pyrrolo[1,2-a]pyrazin-2-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide as a beige solid (75 mg, 0.139 mmol), in 65% yield.¹H NMR (400 MHz, CDCl₃) δ ppm 1.23-1.52 (m, 4H) 1.72-1.90 (m, 2H)1.90-2.00 (m, 6H) 2.00-2.18 (m, 2H) 2.21-2.39 (m, 1H) 2.52-2.82 (m, 3H)2.95-3.14 (m, 3H) 3.15-3.27 (m, 8H) 3.42 (t, J=8.28 Hz, 1H) 3.66 (dt,J=11.54, 4.02 Hz, 1H) 3.95 (ddd, J=11.80, 9.29, 4.52 Hz, 1H) 4.27-4.41(m, 1H) 6.45 (s, 1H) 7.69 (dd, J=9.03, 2.51 Hz, 1H) 8.11 (s, 1H) 8.25(d, J=2.51 Hz, 1H) 8.65 (d, J=9.03 Hz, 1H) 8.73 (s, 1H); HRMS calc form/z=503.2883 and found m/z=503.2892 (M+H).

Example 99

7-Cyclopentyl-2-[5-(1-oxo-octahydro-pyrido[1,2-a]pyrazin-2-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide.

Step 1:

Preparation of2-(6-Nitro-pyridin-3-yl)hexahydro-pyrido[1,2-a]pyrazin-1-one

Following general N—C coupling procedure 1,hexahydro-pyrido[1,2-a]pyrazin-1-one (0.300 g, 1.945 mmol), was combinedwith 5-bromo-2-nitropyridine (0.395 g, 1.945 mmol, 1.0 eq), and gave2-(6-Nitro-pyridin-3-yl)-hexahydro-pyrido[1,2-a]pyrazin-1-one (0.481 g,1.567 mmol) in 81% yield. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.27-1.53 (m,2H) 1.54-1.61 (m, 4H) 1.66-1.81 (m, 1H) 1.94 (d, J=12.55 Hz, 1H) 2.22(td, J=11.80, 3.01 Hz, 1H) 2.39 (d, J=12.55 Hz, 1H) 2.68-2.83 (m, 2H)2.96-3.12 (m, 2H) 3.49 (d, J=3.51 Hz, 1H) 3.56 (dd, J=10.79, 2.26 Hz,1H) 4.16 (td, J=11.29, 4.52 Hz, 1H) 8.13 (dd, J=8.53, 2.51 Hz, 1H) 8.29(d, J=8.53 Hz, 1H) 8.68 (d, J=2.51 Hz, 1H); MS m/z 277.2 (M+H)⁺.

Step 2:

Preparation of2-(6-Amino-pyridin-3-yl)-hexahydro-pyrido[1,2-a]pyrazin-1-one

Following nitro group reduction procedure 1,2-(6-Nitro-pyridin-3-yl)-hexahydro-pyrido[1,2-a]pyrazin-1-one (0.200 g,0.724 mmol), was converted to2-(6-Amino-pyridin-3-yl)-hexahydro-pyrido[1,2-a]pyrazin-1-one (0.170 g,0.690 mmol) in 95% yield. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.28-1.55 (m,1H) 1.53-1.77 (m, 1H) 1.91 (d, J=12.05 Hz, 1H) 2.19 (td, J=11.42, 3.26Hz, 1H) 2.33-2.48 (m, 1H) 2.60-2.75 (m, 1H) 2.89-3.06 (m, 1H) 3.39 (dd,J=11.54, 3.01 Hz, 1H) 3.93 (td, J=11.80, 4.52 Hz, 1H) 4.46 (br. s., 1H)6.51 (d, J=8.53 Hz, 1H) 7.37 (dd, J=8.53, 2.51 Hz, 1H) 7.99 (d, J=2.51Hz, 1H)

MS m/z 247.2 (M+H)⁺.

Step 3:

Preparation of7-Cyclopentyl-2-[5-(1-oxo-octahydro-pyrido[1,2-a]pyrazin-2-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Following general N—C coupling procedure 1,2-(6-Amino-pyridin-3-yl)-hexahydro-pyrido[1,2-a]pyrazin-1-one (0.060 g,0.244 mmol) was combined with2-Chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic aciddimethylamide (0.072 g, 0.246 mmol, 1.01 eq) which gave7-Cyclopentyl-2-[5-(1-oxo-octahydro-pyrido[1,2-a]pyrazin-2-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide, (0.070 g, 0.136 mmol) in 56% yield. ¹H NMR (400 MHz,CDCl₃) δ ppm 1.31-1.50 (m, 2H) 1.66-1.82 (m, 4H) 1.91 (br. s., 1H)1.98-2.14 (m, 5H) 2.21 (td, J=11.42, 3.26 Hz, 1H) 2.40 (br. s., 1H) 2.58(dd, J=12.30, 8.78 Hz, 2H) 2.67-2.81 (m, 2H) 2.93-3.07 (m, 2H) 3.16 (s,7H) 3.47 (dd, J=11.29, 3.26 Hz, 1H) 4.02 (td, J=11.67, 4.77 Hz, 1H) 4.79(dq, J=9.03, 8.87 Hz, 1H) 6.46 (s, 1H) 7.66 (dd, J=9.03, 2.51 Hz, 1H)7.94 (s, 1H) 8.23 (d, J=2.01 Hz, 1H) 8.54 (d, J=9.03 Hz, 1H) 8.71 (s,1H)

HRMS calc for m/z=503.2883 and found m/z=503.2908 (M+H)

Example 100

Preparation of7-Cyclohexyl-2-[5-(1-oxo-octahydro-pyrido[1,2-a]pyrazin-2-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Following general N—C coupling procedure 1,2-(6-Amino-pyridin-3-yl)-hexahydro-pyrido[1,2-a]pyrazin-1-one (0.060 g,0.244 mmol) was combined with2-Chloro-7-cyclohexyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic aciddimethylamide (0.075 g, 0.244 mmol, 1.0 eq) which gave7-Cyclohexyl-2-[5-(1-oxo-octahydro-pyrido[1,2-a]pyrazin-2-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide (0.020 g, 0.039 mmol) in 16% yield. ¹H NMR (400 MHz,CDCl₃) δ ppm 1.19-1.41 (m, 6H) 1.41-1.52 (m, 5H) 1.61-1.75 (m, 4H) 1.93(br. s., 9H) 2.21 (td, J=11.37, 3.54 Hz, 2H) 2.40 (br. s., 2H) 2.52-2.81(m, 7H) 2.93-3.05 (m, 4H) 3.16 (s, 11H) 3.47 (dd, J=11.37, 2.78 Hz, 2H)3.93-4.09 (m, 2H) 4.26-4.42 (m, 2H) 6.44 (s, 2H) 7.68 (dd, J=8.84, 2.78Hz, 2H) 8.00 (s, 2H) 8.23 (d, J=2.02 Hz, 2H) 8.63 (d, J=9.09 Hz, 2H)8.71 (s, 2H) HRMS calc for m/z=517.3039 and found m/z=517.3046 (M+H)

Example 101

7-cyclopentyl-N,N-dimethyl-2-(5-((1R,3r,5S)-2′-oxo-8-azaspiro[bicyclo[3.2.1]octane-3,5′-oxazolidine]-3′-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

Step 1:

Preparation of(1R,3r,5S)-3′-(6-nitropyridin-3-yl)-8-azaspiro[bicyclo[3.2.1]octane-3,5′-oxazolidin]-2′-one

Following general N—C coupling procedure 1,(1R,3r,5S)-8-azaspiro[bicyclo[3.2.1]octane-3,5′-oxazolidin]-2′-one(0.488 g, 1.728 mmol) (Reference: German Patent DE10 2005 030051A1 (28Dec. 2006)) was combined with 5-bromo-2-nitropyridine (0.351 g, 1.728,1.0 eq) which gave(1R,3r,5S)-3′-(6-nitropyridin-3-yl-8-azaspiro[bicyclo[3.2.1]octane-3,5′-oxazolidin]-2′-one(0.615 g, 1.521 mmol) 88% yield. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.49 (s,9H) 1.91-2.10 (m, 4H) 2.10-2.33 (m, 6H) 3.81 (s, 2H) 4.32 (br. s., 1H)4.37 (br. s., 1H) 8.32 (d, J=8.53 Hz, 1H) 8.47-8.57 (m, 2H); MS m/z405.2 (M+H)⁺.

Step 2:

Preparation of(1R,3r,5S)-3′-(6-aminopyridin-3-yl)-8-azaspiro[bicyclo[3.2.1]octane-3,5′-oxazolidin]-2′-one

Following nitro group reduction procedure 1,(1R,3R,5S)-3′-(6-nitropyridin-3-yl)-8-azaspiro[bicyclo[3.2.1]octane-3,5′-oxazolidin]-2′-one(0.705 g, 1.743 mmol) was converted to(1R,3r,5S)-3′-(6-aminopyridin-3-yl)-8-azaspiro[bicyclo[3.2.1]octane-3,5′-oxazolidin]-2′-oneas an off-white solid (0.356 g, 0.951 mmol) 55% yield. ¹H NMR (400 MHz,CDCl₃) δ ppm 1.48 (s, 9H) 1.99 (br. s., 4H) 2.07-2.19 (m, 3H) 2.23 (d,J=6.02 Hz, 2H) 3.63 (s, 2H) 4.27 (br. s., 1H) 4.35 (br. s., 1H) 4.43(br. s., 2H) 6.55 (d, J=9.03 Hz, 1H) 7.27 (s, 1H) 7.85-7.91 (m, 1H) 7.93(d, J=2.51 Hz, 1H)

MS m/z 375.2 (M+H)⁺.

Step 3:

Preparation of (1R,3r,5S)-tert-butyl3′-(6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)pyridin-3-yl)-2′-oxo-8-azaspiro[bicyclo[3.2.1]octane-3,5′-oxazolidine]-8-carboxylate

Following general N—C coupling procedure 1,(1R,3r,5S)-3′-(6-aminopyridin-3-yl)-8-azaspiro[bicyclo[3.2.1]octane-3,5-oxazolidin]-Z-onewas combined with2-Chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic aciddimethylamide which gave (1R,3r,5S)-tert-butyl3′-(6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)pyridin-3-yl)-2′-oxo-8-azaspiro[bicyclo[3.2.1]octane-3,5′-oxazolidine]-8-carboxylateas a dark solid (0.458 g, 0.726 mmol) in 78% yield and used in next stepwithout purification. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.49 (s, 9H)1.66-1.81 (m, 2H) 1.98-2.27 (m, 12H) 2.48-2.67 (m, 2H) 3.16 (s, 6H) 3.72(s, 2H) 4.36 (br. s., 2H) 4.80 (dq, J=9.03, 8.87 Hz, 1H) 6.46 (s, 1H)8.03-8.11 (m, 2H) 8.26 (d, J=3.01 Hz, 1H) 8.51 (d, J=9.03 Hz, 1H) 8.74(s, 1H). MS m/z 631.4 (M+H)⁺.

Step 4:

Preparation of7-cyclopentyl-N,N-dimethyl-2-(5-((1R,3r,5S)-2′-oxo-8-azaspiro[bicyclo[3.2.1]octane-3,5′-oxazolidine]-3′-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

Following deprotection method 1, (1R,3r,5S)-tert-butyl3′-(6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)pyridin-3-yl)-2′-oxo-8-azaspiro[bicyclo[3.2.1]octane-3,5′-oxazolidine]-8-carboxylate(0.450 g, 0.713 mmol) was converted to7-cyclopentyl-N,N-dimethyl-2-(5-((1R,3r,5S)-2′-oxo-8-azaspiro[bicyclo[3.2.1]octane-3,5′-oxazolidine]-3′-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide(0.286 g, 0.517 mmol) in 73% yield. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.62(br. s., 1H) 1.66-1.84 (m, 4H) 1.93-2.14 (m, 7H) 2.20 (d, J=14.56 Hz,2H) 2.24-2.37 (m, 2H) 2.47-2.68 (m, 2H) 3.16 (s, 6H) 3.65 (br. 5., 2 H)3.71 (s, 2H) 4.80 (quin, J=8.78 Hz, 1H) 6.46 (s, 1H) 8.08 (dd, J=9.03,2.51 Hz, 1H) 8.19-8.32 (m, 2H) 8.50 (d, J=9.03 Hz, 1H) 8.75 (s, 1H);HRMS calc for m/z=531.2832 and found m/z=531.2858 (M+H)⁺.

Example 102

Preparation of7-cyclopentyl-N,N-dimethyl-2-(5-((1R,3r,5S)-8-methyl-2′-oxo-8-azaspiro[bicyclo[3.2.1]octane-3,5′-oxazolidine]-3′-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

Preparation of7-cyclopentyl-N,N-dimethyl-2-(5-((1R,3r,5S)-8-methyl-2′-oxo-8-azaspiro[bicyclo[3.2.1]octane-3,5′-oxazolidine]-3′-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

Following general reductive alkylation method1,7-cyclopentyl-N,N-dimethyl-2-(5-((1R,3r,5S)-2′-oxo-8-azaspiro[bicyclo[3.2.1]octane-3,5′-oxazolidine]-3′-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide(0.216 g, 0.407 mmol) was converted to7-cyclopentyl-N,N-dimethyl-2-(5-((1R,3r,5S)-8-methyl-2′-oxo-8-azaspiro[bicyclo[3.2.1]octane-3,5′-oxazolidine]-3′-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamideas an white solid (0.120 g, 0.220 mmol) in 54% yield. ¹H NMR (400 MHz,CDCl₃) δ ppm 1.52-1.82 (m, 4H) 1.93-2.11 (m, 7H) 2.11-2.25 (m, 6H) 2.34(br. s., 4H) 2.48-2.68 (m, 2H) 3.16 (s, 6H) 3.25 (br. s., 2H) 3.71 (s,2H) 4.80 (qd, J=8.95, 8.78 Hz, 1H) 6.46 (s, 1H) 7.98 (s, 1H) 8.07 (dd,J=9.29, 2.76 Hz, 1H) 8.23 (d, J=2.51 Hz, 1H) 8.49 (d, J=9.54 Hz, 1H)8.72 (s, 1H)

HRMS calc for m/z=545.2989 and found m/z=545.2988 (M+H)⁺.

Example 103

7-cyclopentyl-N,N-dimethyl-2-(5-(2-oxo-1-oxa-3,8-diazaspiro[4.6]undecan-3-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

Step 1:

Preparation of3-(6-Nitro-pyridin-3-yl)-2-oxo-1-oxa-3,8-diaza-spiro[4.6]undecane-8-carboxylicacid tert-butyl ester

Following general N—C coupling procedure 1,2-oxo-1-oxa-3,8-diaza-spiro[4.6]undecane-8-carboxylic acid tert-butylester (0.510 g, 1.887 mmol) (Reference: German Patent DE10 2005 030051A1(28 Dec. 2006)) was combined with 5-bromo-2-nitropyridine (0.400 g,1.971 mmol, 1.05 eq) which gave3-(6-Nitro-pyridin-3-yl)-2-oxo-1-oxa-3,8-diaza-spiro[4.6]undecane-8-carboxylicacid tert-butyl ester as a brown solid (0.684 g, 1.743 mmol) in 92%yield. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.45 (br. s., 9H) 1.54-1.72 (m, 1H)1.86-2.16 (m, 3H) 3.30 (d, J=8.03 Hz, 1H) 3.66 (br. s., 2H) 3.81 (d,J=9.03 Hz, 1H) 3.94 (d, J=7.53 Hz, 1H) 8.33 (d, J=9.03 Hz, 1H) 8.52 (br.s., 1H) 8.60 (dd, J=9.03, 3.01 Hz, 1H). MS m/z 337.1 (M+H)⁺

Step 2:

Preparation of3-(6-Amino-pyridin-3-yl)-2-oxo-1-oxa-3,8-diaza-spiro[4.6]undecane-8-carboxylicacid tert-butyl ester

Following nitro group reduction procedure 1,3-(6-Nitro-pyridin-3-yl)-1-oxa-3,8-diaza-spiro[4.6]undecan-2-one (0.620g, 1.580 mmol) was converted to3-(6-Amino-pyridin-3-yl)-2-oxo-1-oxa-3,8-diaza-spiro[4.6]undecane-8-carboxylicacid tert-butyl ester as an off-white solid (0.532 g, 1.47 mmol) 93%yield. ¹H NMR (400 MHz, CDCl₃) O ppm 1.47 (s, 9H) 1.80 (dd, J=13.55,9.54 Hz, 2H) 1.86-2.01 (m, 1H) 2.06-2.24 (m, 3H) 3.18-3.34 (m, 2H)3.58-3.80 (m, 4H) 4.40 (br. 5., 2 H) 6.54 (d, J=8.53 Hz, 1H) 7.87-7.97(m, 2H). MS m/z 363.2 (M+H)⁴.

Step 3:

Preparation of7-cyclopentyl-N,N-dimethyl-2-(5-(2-oxo-1-oxa-3,8-diazaspiro[4.6]undecan-3-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

Following general N—C coupling procedure 1,3-(6-Amino-pyridin-3-yl)-1-oxa-3,8-diaza-spiro[4.6]undecan-2-one (0.100g, 0.276 mmol) was combined with2-Chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic aciddimethylamide (0.081 g, 0.276 mmol, 1.0 eq) which gave7-cyclopentyl-N,N-dimethyl-2-(5-(2-oxo-1-oxa-3,8-diazaspiro[4.6]undecan-3-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamideas white solid (0.075 g, 0.139 mmol) in 50% yield. ¹H NMR (400 MHz,CDCl₃) 6 ppm 1.58-1.82 (m, 4H) 1.97-2.27 (m, 14H) 2.47-2.65 (m, 2H)2.86-3.11 (m, 4H) 3.16 (s, 7H) 3.80-3.88 (m, 2H) 4.80 (qd, J=8.95, 8.78Hz, 1H) 6.46 (s, 1H) 8.06 (s, 1H) 8.13 (dd, J=9.03, 3.01 Hz, 1H)8.21-8.32 (m, 1H) 8.50 (d, J=9.03 Hz, 1H) 8.72 (s, 1H); HRMS calc form/z=531.2832 and found m/z=531.2858 (M+H)⁺.

Example 104

7-Cyclopentyl-2-[5-(8-methyl-2-oxo-1-oxa-3,8-diaza-spiro[4.6]undec-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Step 1

7-cyclopentyl-N,N-dimethyl-2-(5-(8-methyl-2-oxo-1-oxa-3,8-diazaspiro[4.6]undecan-3-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

Following general reductive alkylation method1,7-cyclopentyl-N,N-dimethyl-2-(5-(2-oxo-1-oxa-3,8-diazaspiro[4.6]undecan-3-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamidewas converted to7-cyclopentyl-N,N-dimethyl-2-(5-(8-methyl-2-oxo-1-oxa-3,8-diazaspiro[4.6]undecan-3-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide(0.062 g, 0.112 mmol) in 77% yield. ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.52-1.79 (m, 5H) 1.84-2.05 (m, 8H) 2.07 (t, J=5.27 Hz, 2H) 2.28 (s, 3H)3.06 (d, J=10.54 Hz, 7H) 3.90 (s, 2H) 4.68-4.84 (m, 1H) 6.63 (s, 1H)7.99 (dd, J=9.03, 2.51 Hz, 1H) 8.33 (d, J=9.03 Hz, 1H) 8.43 (d, J=2.51Hz, 1H) 8.80 (s, 1H) 9.73 (s, 1H);

HRMS calc for m/z=533.2989 and found m/z=533.3009 (M+H)⁺.

Example 105

7-Cyclopentyl-2-[5-((S)-2-oxo-1-oxa-3,8-diaza-spiro[4.6]undec-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Step 1:

Preparation of(S)-3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-2-oxo-1-oxa-3,8-diaza-spiro[4.6]undecane-8-carboxylicacid tert-butyl ester

Following general N—C coupling procedure 1,(S)-3-(6-Amino-pyridin-3-yl)-2-oxo-1-oxa-3,8-diaza-spiro[4.6]undecane-8-carboxylicacid tert-butyl ester was combined with2-Chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic aciddimethylamide which gave(S)-3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-2-oxo-1-oxa-3,8-diaza-spiro[4.6]undecane-8-carboxylicacid tert-butyl ester as a white solid (0.075 g, 0.115 mmol) in 35%yield. MS m/z 619.5 (M+H)⁺.

Step 2:

Preparation of7-Cyclopentyl-2-[5-((S)-2-oxo-1-oxa-3,8-diaza-spiro[4.6]undec-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Following deprotection method 1,(S)-3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-2-oxo-1-oxa-3,8-diaza-spiro[4.6]undecane-8-carboxylicacid tert-butyl ester was converted to7-Cyclopentyl-2-[5-((S)-2-oxo-1-oxa-3,8-diaza-spiro[4.6]undec-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide as a white solid (0.040 g, 0.076 mmol) in 67% yield.¹H NMR (400 MHz, MeOD) δ ppm 1.67-1.86 (m, 3H) 1.91-2.17 (m, 8H)2.19-2.28 (m, 2H) 2.49-2.65 (m, 2H) 2.86-3.09 (m, 4H) 3.11-3.21 (m, 7H)3.95 (s, 2H) 4.78 (dq, J=9.03, 8.87 Hz, 1H) 8.05 (dd, J=9.03, 3.01 Hz,1H) 8.40-8.49 (m, 2H) 8.75 (5, 1H); HRMS calc for m/z=519.2832 and foundm/z=519.2842 (M+H)⁺.

Example 106

7-Cyclopentyl-2-[5-((R)-2-oxo-1-oxa-3,8-diaza-spiro[4.6]undec-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Step 1

Preparation of(R)-3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-2-oxo-1-oxa-3,8-diaza-spiro[4.6]undecane-8-carboxylicacid tert-butyl ester

Following general N—C coupling procedure 1,(R)-3-(6-Amino-pyridin-3-yl)-2-oxo-1-oxa-3,8-diaza-spiro[4.6]undecane-8-carboxylicacid tert-butyl ester was combined with2-Chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic aciddimethylamide which gave(R)-3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-2-oxo-1-oxa-3,8-diaza-spiro[4.6]undecane-8-carboxylicacid tert-butyl ester as a white solid (0.175 g, 0.272 mmol) in 66%yield. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.42 (s, 9H) 1.61-1.78 (m, 3H)1.79-1.96 (m, 3H) 1.96-2.14 (m, 7H) 2.38-2.48 (m, 2H) 3.06 (d, J=10.54Hz, 6H) 3.20-3.33 (m, 2H) 3.36-3.63 (m, 2H) 3.82-3.97 (m, 2H) 4.75(quin, J=8.78 Hz, 1H) 6.63 (s, 1H) 7.98 (d, J=9.03 Hz, 1H) 8.34 (d,J=9.54 Hz, 1H) 8.44 (s, 1H) 8.81 (s, 1H) 9.78 (s, 1H). MS m/z 619.5(M+H)⁺.

Step 2

Preparation of7-Cyclopentyl-2-[5-((R)-2-oxo-1-oxa-3,8-diaza-spiro[4.6]undec-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Following deprotection method 1,(R)-3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-2-oxo-1-oxa-3,8-diaza-spiro[4.6]undecane-8-carboxylicacid tert-butyl ester was converted to7-Cyclopentyl-2-[5-((R)-2-oxo-1-oxa-3,8-diaza-spiro[4.6]undec-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide as a white solid (0.090 g, 0.167 mmol) in 70% yield.¹H NMR (400 MHz, MeOD) δ ppm 1.65-1.86 (m, 3H) 1.97 (dd, J=10.79, 4.27Hz, 1H) 2.01-2.29 (m, 9H) 2.46-2.64 (m, 2H) 2.88-3.11 (m, 4H) 3.13-3.22(m, 6H) 3.94 (s, 2H) 4.77 (dq, J=9.03, 8.87 Hz, 1H) 6.63 (s, 1H) 8.04(dd, J=9.29, 2.76 Hz, 1H) 8.40-8.49 (m, 2H) 8.76 (s, 1H). HRMS caic form/z=519.2832 and found m/z=519.2834 (M+H)⁺.

Example 107

7-cyclopentyl-N,N-dimethyl-2-(5-(2-oxo-1-oxa-3,7-diazaspiro[4.5]decan-3-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

Step 1:

Preparation of3-(6-Nitro-pyridin-3-yl)-2-oxo-1-oxa-3,7-diaza-spiro[4.5]decane-7-carboxylicacid tert-butyl ester

Following general N—C coupling procedure 1,2-oxo-1-oxa-3,7-diaza-spiro[4.5]decane-7-carboxylic acid tert-butylester (0.546 g, 2.130 mmol) (Reference: German Patent DE10 2005 030051A1(28 Dec. 2006)), was combined with 5-bromo-2-nitropyridine (0.432 g,2.130 mmol, 1.0 eq) which gave3-(6-Nitro-pyridin-3-yl)-2-oxo-1-oxa-3,7-diaza-spiro[4.5]decane-7-carboxylicacid tert-butyl ester as a brown solid (0.709 g, 1.735 mmol) in 81%yield. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.46 (br. s., 9H) 1.55-1.73 (m, 2H)1.89-2.17 (m, 3H) 3.41 (br. s., 2H) 3.65 (br. s., 2H) 3.78-3.88 (m, 1H)3.95 (d, J=8.03 Hz, 1H) 8.34 (d, J=9.03 Hz, 1H) 8.54 (br. s., 1H) 8.61(dd, J=9.03, 3.01 Hz, 1H) MS m/z 379.1 (M+H)⁺.

Step 2:

Preparation of3-(6-Amino-pyridin-3-yl)-2-oxo-1-oxa-3,7-diaza-spiro[4.5]decane-7-carboxylicacid tert-butyl ester

Following nitro group reduction procedure 1,3-(6-Nitro-pyridin-3-yl)-2-oxo-1-oxa-3,7-diaza-spiro[4.5]decane-7-carboxylicacid tert-butyl ester (0.605 g, 1.599 mmol) was converted to3-(6-Amino-pyridin-3-yl)-2-oxo-1-oxa-3,7-diaza-spiro[4.5]decane-7-carboxylicacid tert-butyl ester (0.549 g, 1.45 mmol) in 92% yield. ¹H NMR (400MHz, CDCl₃) δ ppm 1.45 (s, 1H) 1.50-1.70 (m, 1H) 1.79-2.08 (m, 1H) 3.21(t, J=10.04 Hz, 1H) 3.31-3.47 (m, 1H) 3.65 (d, J=9.03 Hz, 1H) 3.70-3.85(m, 1H) 4.41 (br. s., 1H) 6.55 (d, J=8.53 Hz, 1H) 7.91 (dd, J=8.78, 2.76Hz, 1H) 7.96 (d, J=2.51 Hz, 1H). MS m/z 349.1 (M+H)⁺.

Step 3:

Preparation of3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-2-oxo-1-oxa-3,7-diaza-spiro[4.5]decane-7-carboxylicacid tert-butyl ester

Following general N—C coupling procedure 1,3-(6-Amino-pyridin-3-yl)-2-oxo-1-oxa-3,7-diaza-spiro[4.5]decane-7-carboxylicacid tert-butyl ester was combined with2-Chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic aciddimethylamide (0.084 g, 0.287 mmol, 1.0 eq) and gave3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-2-oxo-1-oxa-3,7-diaza-spiro[4.5]decane-7-carboxylicacid tert-butyl ester which was used directly in the following BOCdeprotection.

Step 4

Preparation of7-cyclopentyl-N,N-dimethyl-2-(5-(2-oxo-1-oxa-3,7-diazaspiro[4.5]decan-3-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

Following deprotection method 1,3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-2-oxo-1-oxa-3,7-diaza-spiro[4.5]decane-7-carboxylicacid tert-butyl ester was converted to7-cyclopentyl-N,N-dimethyl-2-(5-(2-oxo-1-oxa-3,7-diazaspiro[4.5]decan-3-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamidewhich gave a white solid (0.070 g, 0.135 mmol in 47% yield. ¹H NMR (400MHz, CDCl₃) δ ppm 1.54-1.68 (m, 1H) 1.68-1.81 (m, 2H) 1.81-1.98 (m, 4H)1.98-2.14 (m, 6H) 2.46-2.69 (m, 2H) 2.77-2.91 (m, 2H) 2.91-3.12 (m, 2H)3.16 (s, 6H) 3.75 (d, J=8.53 Hz, 1H) 3.91 (d, J=8.53 Hz, 1H) 4.80 (dq,J=9.03, 8.87 Hz, 1H) 6.46 (s, 1H) 8.13 (dd, J=9.03, 3.01 Hz, 1H) 8.33(br. s., 1H) 8.36 (d, J=2.51 Hz, 1H) 8.51 (d, J=9.03 Hz, 1H) 8.76 (s,1H). HRMS calc for m/z=505.2676 and found m/z=505.2676 (M+H)⁺.

Example 108

Preparation of7-cyclopentyl-N,N-dimethyl-2-(5-(7-methyl-2-oxo-1-oxa-3,7-diazaspiro[4.5]decan-3-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

Following general reductive alkylation method1,7-cyclopentyl-N,N-dimethyl-2-(5-(2-oxo-1-oxa-3,7-diazaspiro[4.5]decan-3-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide(0.116 mmol) was converted to7-cyclopentyl-N,N-dimethyl-2-(5-(7-methyl-2-oxo-1-oxa-3,7-diazaspiro[4.5]decan-3-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamidewhich was isolated as an off-white solid (0.052 g, 0.098 mmol) in 85%yield. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.51-1.79 (m, 6H) 1.85 (br. s.,1H) 1.99 (s, 5H) 2.09 (br. s., 1H) 2.22 (s, 4H) 2.37-2.48 (m, 3H) 2.68(d, J=8.03 Hz, 1H) 3.06 (d, J=11.04 Hz, 7H) 3.86-3.98 (m, 2H) 4.69-4.83(m, 1H) 6.63 (s, 1H) 8.03 (dd, J=9.29, 2.76 Hz, 1H) 8.34 (d, J=9.03 Hz,1H) 8.48 (d, J=3.01 Hz, 1H) 8.81 (s, 1H) 9.74 (s, 1H). HRMS calc form/z=519.2832 and found m/z=519.2834 (M+H)⁺.

Example 109

7-Cyclopentyl-2-[5-((S)-2-oxo-1-oxa-3,7-diaza-spiro[4.5]dec-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Step 1:

Preparation of(S)-3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-2-oxo-1-oxa-3,7-diaza-spiro[4.5]decane-7-carboxylicacid tert-butyl ester

Following general N—C coupling procedure 1,(S)-3-(6-Amino-pyridin-3-yl)-2-oxo-1-oxa-3,7-diaza-spiro[4.5]decane-7-carboxylicacid tert-butyl ester was combined with2-Chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic aciddimethylamide which gave(S)-3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-2-oxo-1-oxa-3,7-diaza-spiro[4.5]decane-7-carboxylicacid tert-butyl ester as a white solid (0.115 g, 0.190 mmol in 43%yield. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.37-1.51 (m, 13H) 1.51-1.69 (m,3H) 1.69-1.84 (m, 2H) 1.85-2.15 (m, 11H) 2.47-2.68 (m, 2H) 3.10-3.19 (m,6H) 3.19-3.33 (m, 2H) 3.43 (d, J=14.05 Hz, 1H) 3.58-3.71 (m, 2H)3.71-3.80 (m, 2H) 3.85 (d, J=9.03 Hz, 2H) 4.12 (q, J=7.03 Hz, 1H) 4.44(br. s., 1H) 4.80 (quin, J=8.78 Hz, 1H) 6.46 (s, 1H) 7.87-7.99 (m, 1H)8.11 (dd, J=9.29, 2.76 Hz, 1H) 8.21 (br. s., 1H) 8.30 (br. s., 1H) 8.52(d, J=9.03 Hz, 1H) 8.75 (s, 1H). MS m/z 605.5 (M+H)⁺.

Step 2:

Preparation of7-Cyclopentyl-2-[5-((S)-2-oxo-1-oxa-3,7-diaza-spiro[4.5]dec-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Following de protection method 1,(S)-3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-2-oxo-1-oxa-3,7-diaza-spiro[4.5]decane-7-carboxylicacid tert-butyl ester was converted to7-Cyclopentyl-2-[5-((S)-2-oxo-1-oxa-3,7-diaza-spiro[4.5]dec-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide (0.062 g, 0.123 mmol) in 71% yield. ¹H NMR (400 MHz,MeOD) δ ppm 1.66 (ddd, J=9.66, 6.65, 3.26 Hz, 1H) 1.70-1.81 (m, 2H)1.81-2.00 (m, 2H) 2.00-2.16 (m, 5H) 2.47-2.64 (m, 2H) 2.66-2.80 (m, 1H)2.80-2.90 (m, 1H) 2.90-2.99 (m, 1H) 2.99-3.10 (m, 1H) 3.16 (d, J=4.52Hz, 7H) 3.83-3.90 (m, 1H) 3.90-3.99 (m, 1H) 4.78 (dq, J=9.03, 8.87 Hz,1H) 8.07 (dd, J=9.29, 2.76 Hz, 1H) 8.44 (s, 1H) 8.46 (d, J=5.02 Hz, 1H)8.75 (s, 1H). HRMS calc for m/z=505.2676 and found m/z=505.2683 (M+H)⁺.

Example 110

7-Cyclopentyl-2-[5-((R)-2-oxo-1-oxa-3,7-diaza-spiro[4.5]dec-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Step 1

Preparation of(R)-3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-2-oxo-1-oxa-3,7-diaza-spiro[4.5]decane-7-carboxylicacid tert-butyl ester

Following general N—C coupling procedure 1,(R)-3-(6-amino-pyridin-3-yl)-2-oxo-1-oxa-3,7-diaza-spiro[4.5]decane-7-carboxylicacid tert-butyl ester was combined with2-Chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic aciddimethylamide which gave(R)-3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-2-oxo-1-oxa-3,7-diaza-spiro[4.5]decane-7-carboxylicacid tert-butyl ester as a white solid (0.175 g, 0.275 mmol) in 64%yield. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.47 (s, 9H) 1.55-1.68 (m, 2H)1.68-1.85 (m, 3H) 1.88-2.18 (m, 8H) 2.50-2.68 (m, 2H) 3.13-3.21 (m, 6H)3.21-3.32 (m, 1H) 3.37-3.58 (m, 1H) 3.61-3.72 (m, 1H) 3.75 (d, J=8.53Hz, 2H) 3.86 (d, J=8.53 Hz, 2H) 4.72-4.95 (m, J=8.91, 8.91, 8.78, 8.53Hz, 1H) 6.48 (s, 1H) 8.14 (dd, J=9.29, 2.76 Hz, 1H) 8.31 (br. s., 1H)8.53 (d, J=9.54 Hz, 1H) 8.76 (s, 1H). MS m/z 605.5 (M+H)⁺.

Step 2

7-Cyclopentyl-2-[5-((R)-2-oxo-1-oxa-3,7-diaza-spiro[4.5]dec-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Following deprotection method 1,(R)-3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-2-oxo-1-oxa-3,7-diaza-spiro[4.5]decane-7-carboxylicacid tert-butyl ester was converted to7-Cyclopentyl-2-[5-((R)-2-oxo-1-oxa-3,7-diaza-spiro[4.5]dec-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide as a white solid (0.120 g, 0.238 mmol) in 85% yield.

¹H NMR (400 MHz, MeOD) δ ppm 1.66 (ddd, J=9.79, 6.53, 3.26 Hz, 1H)1.70-1.81 (m, 2H) 1.81-2.01 (m, 2H) 2.01-2.18 (m, 5H) 2.47-2.64 (m, 2H)2.69-2.82 (m, 1H) 2.85 (d, J=6.02 Hz, 1H) 2.91-2.99 (m, 1H) 2.99-3.09(m, 1H) 3.10-3.20 (m, 6H) 3.82-3.90 (m, 1H) 3.90-3.99 (m, 1H) 4.78 (qd,J=8.95, 8.78 Hz, 1H) 6.63 (s, 1H) 8.07 (dd, J=9.54, 2.51 Hz, 1H) 8.44(s, 1H) 8.46 (d, J=5.02 Hz, 1H) 8.75 (s, 1H)

HRMS talc for m/z=505.2676 and found m/z=505.2676 (M+H)⁺.

Example 111

7-Cyclopentyl-2-[5-(2,5-diaza-bicyclo[2.2.1]hept-2-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Step 1:

Preparation of5-(6-Nitro-pyridin-3-yl)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylicacid tert-butyl ester

2-Bromo-5-Nitropyridine (4.75 g, 23.4 mmol, 1.0 eq) and(R,R)-2,5-Diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester(5.04 g, 25.4 mmol, 1.1 eq) were combined in DMF (60 mL) and heated to100° C. The reaction was cooled and diluted with Ethyl Acetate, washedwith water several times followed by brine, the organic layer dried(Na₂SO₄), filtered, and the organic concentrated. Crude was purifiedusing chromatography eluting with MeOH/DCM mixtures giving the desiredproduct (4.3 g, 57%). MS m/z 278.4 (M-C₄H₉).

Step 2:

5-(6-Amino-pyridin-3-yl)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylicacid tert-butyl ester5-(6-Nitro-pyridin-3-yl)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylicacid tert-butyl ester (1.00 g, 3.12, ol, 1.0 eq) was hydrogenated in aparr flask at 50 psi using Pd/C (0.250 g) in Ethyl Acetate (25 mL) for16 hr. The reaction contents were filtered through Celite was washedwith MeOH and the filtrate was concentrated. The crude was purifiedchromatographically using (MeOH/CH₂Cl₂) mixtures giving a purple solid(0.648 g, 68%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.44 (d, J=19.71Hz, 12H) 1.84-2.07 (m, 3H) 3.11 (d, J=8.59 Hz, 1H) 3.29-3.51 (m, 3H)3.52-3.60 (m, 1H) 4.02 (br. s., 2H) 4.29 (s, 1H) 6.46-6.55 (m, 1H) 6.84(dd, J=8.59, 2.53 Hz, 1H) 7.50 (br. s., 1H); MS m/z 291.6 (M+H)⁺.

Step 3:

Preparation of4-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-1-carboxylicacid tert-butyl ester

Using General Buchwald method 1,2-Chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic aciddimethylamide (200 mg, 0.683 mmol, 1.0 eq) was combined with5-(6-Amino-pyridin-3-yl)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylicacid tert-butyl ester (218 mg, 0.751 mmol, 1.1 eq) to give4-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-1-carboxylicacid tert-butyl ester (350 mg, 94% yield). 1H NMR (400 MHz, DMSO-d₆) δppm 1.32 (s, 6H) 1.39 (s, 6H) 1.62 (br. s., 3H) 1.94 (br. s., 8H) 2.41(br. s., 3H) 2.92-3.02 (m, 2H) 3.05 (br. s., 7H) 3.26 (d, J=11.12 Hz,3H) 3.34 (br. s., 3H) 3.51-3.64 (m, 1H) 4.39 (s, 1H) 4.45 (br. s., 1H)4.55 (br. s., 1H) 4.72 (t, J=8.59 Hz, 1H) 6.58 (s, 1H) 7.12 (dd, J=9.09,3.03 Hz, 1H) 7.74 (d, J=2.53 Hz, 1H) 8.02 (t, J=8.08 Hz, 1H) 8.72 (s,1H) 9.15 (s, 1H); MS m/z 547.1 (M+H)⁺.

Step 4:

Preparation of7-Cyclopentyl-2-[5-(2,5-diaza-bicyclo[2.2.1]hept-2-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Treatment of4-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-piperazine-1-carboxylicacid tert-butyl ester with TFA using general deprotection method 2 forremoval of the BOC group gave7-Cyclopentyl-2-[5-(2,5-diaza-bicyclo[2.2.1]hept-2-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide (117 mg, 47%). 1H NMR (400 MHz, DMSO-d₆) δ ppm 1.65(br. s., 3H) 1.79 (s, 1H) 1.90 (s, 1H) 1.93-2.02 (m, 5H) 2.43 (br. s.,3H) 2.82-2.91 (m, 3H) 3.05 (br. s., 6H) 3.49-3.57 (m, 1H) 3.64 (br. s.,1H) 4.37 (s, 1H) 4.67-4.79 (m, 1H) 6.57 (s, 1H) 7.04 (dd, J=9.09, 3.03Hz, 1H) 7.68 (d, J=3.03 Hz, 1H) 8.03 (d, J=9.09 Hz, 1H) 8.71 (s, 1H)9.07 (s, 1H); MS m/z 447.2 (M+H)⁺.

Example 112

7-Cyclopentyl-2-[5(3,8-diaza-bicyclo[3.2.1]oct-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Step 1:

Preparation of3-(6-Nitro-pyridin-3-yl)-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester

Following Example 78 Step 1 using 5-bromo-2-nitropyridine (200 mg, 0.985mmol, 1.0 eq) and (3,8-Diaza-bicyclo[3.2.1]octane-8-carboxylic acidtert-butyl ester (934 mg, 4.40 mmol, 4.5 eq) gave3-(6-Nitro-pyridin-3-yl)-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester (242 mg, 74%). 1H NMR (400 MHz, CHLOROFORM-d) δppm 1.51 (s, 10H) 1.75-1.89 (m, 2H) 2.01-2.12 (m, 2H) 3.27 (d, J=11.12Hz, 2H) 3.59 (d, J=11.62 Hz, 2H) 4.48 (br. s., 2H) 7.17 (dd, J=9.09,3.03 Hz, 1H) 8.10 (d, J=3.03 Hz, 1H) 8.19 (d, J=9.09 Hz, 1H); MS m/z335.1 (M+H)⁺.

Step 2:

Preparation of3-(6-Amino-pyridin-3-yl)-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester

Following Example 78 Step 2 using5-(6-Nitro-pyridin-3-yl)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylicacid tert-butyl ester (240 mg, 0.718 mmol, 1.0 eq) and Pd/C (76 mg) gave3-(6-Amino-pyridin-3-yl)-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester (205 mg, 94%). MS m/z 305.2 (M+H)⁺.

Step 3:

Preparation of3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester

Using General Buchwald method 1,2-Chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic aciddimethylamide (139 mg, 0.476 mmol, 1.0 eq) was combined with3-(6-Amino-pyridin-3-yl)-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester (145 mg, 0.476 mmol, 1.0 eq) to give3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester (143 mg, 51% yield). 1H NMR (400 MHz, DMSO-d₆) δppm 1.42 (s, 9H) 1.57-1.70 (m, 2H) 1.74-1.92 (m, 4H) 1.98 (br. s., 4H)2.36-2.48 (m, 2H) 2.78 (d, J=10.11 Hz, 2H) 3.05 (br. s., 6H) 3.48 (d,J=10.11 Hz, 2H) 4.24 (br. s., 2H) 4.73 (qd, J=8.76, 8.59 Hz, 1H) 6.59(s, 1H) 7.37 (dd, J=9.09, 3.03 Hz, 1H) 7.94 (d, J=3.03 Hz, 1H) 8.13 (d,J=9.09 Hz, 1H) 8.75 (s, 1H) 9.24 (s, 1H); MS m/z 561.3 (M+H).

Step 4:

7-Cyclopentyl-2-[5-(3,8-diaza-bicyclo[3.2.1]oct-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Treatment of3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester with TFA using general deprotection method 2 forremoval of the BOC group gave7-Cyclopentyl-2-[5-(3,8-diaza-bicyclo[3.2.1]oct-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide (83 mg, 76%). 1H NMR (400 MHz, DMSO-d₆) δ ppm1.54-1.72 (m, 2H) 1.86-2.04 (m, 8H) 2.36-2.48 (m, 2H) 2.93-3.11 (m, 8H)3.59 (d, J=10.11 Hz, 2H) 4.06 (br. s., 2H) 4.74 (qd, J=8.76, 8.59 Hz,1H) 6.60 (s, 1H) 7.41 (dd, J=9.35, 2.78 Hz, 1H) 7.97 (d, J=2.53 Hz, 1H)8.16 (d, J=9.09 Hz, 1H) 8.36 (br. s., 1H) 8.75 (s, 1H) 9.30 (s, 1H); MSm/z 461.2 (M+H)

Example 113

Step 1

Preparation of 6-Oxo-1,7-diaza-spiro[4,4]nonan-1-carboxylic acidtert-butyl ester 1

To a solution of 1,7-diazaspiro[4,4]nonan-6-one hydrochloride (0.98 g,5.4 mmol) in dichloromethane were added tert-butyldicarbonate (1.41 g,6.48 mmol) and triethylamine (1.3 g, 13.5 mmol). The resulting solutionwas stirred overnight at room temperature. The solution was diluted withwater and extracted with dichloromethane. The organic phase wasseparated, dried, filtered and concentrated to afford6-oxo-1,7-diaza-spiro[4,4]nonan-1-carboxylic acid tert-butyl esterproduct as white powder (1.3 g) in 100% yield and used directly withoutfurther purification. ¹H NMR (400 MHz, CD₂Cl₂) δ 6.13-5.74 (br, 1H),3.59-3.20 (m, 4H), 2.75-2.49 (m, 1H), 2.16-1.76 (m, 5H), 1.43 (s, 3H),1.42 (s, 6H). MS m/z 241.2 (M+H)⁺

Step 2

Preparation of7-(6-Nitro-pyridin-3-yl)-6-oxo-1,7-diaza-spiro[4,4]nonane-1-carboxylicacid tert-butyl ester

Following general N—C coupling procedure 1,6-oxo-1,7-diaza-spiro[4,4]nonan-1-carboxylic acid tert-butyl ester (1.3g, 5.41 mmol) was combined with 5-bromo-2-nitropyridine (1.10 g, 5.41mmol) which gave7-(6-nitro-pyridin-3-yl)-6-oxo-1,7-diaza-spiro[4,4]nonane-1-carboxylicacid tert-butyl ester (1.55 g) in 79% yield.

¹H NMR (400 MHz, CD₂Cl₂) 8.94-8.81 (m, 1H), 8.68-8.59 (m, 1H), 8.38-8.27(m, 1H), 4.17-3.74 (m 2H), 3.66-3.45 (m, 2H), 2.88-2.58 (m, 1H),2.26-1.87 (m, 5H), 1.46 9s, 3H), 1.32 (s, 6H). HR-MS m/z 368.1620 (M+H)⁺

Step 2

Preparation of7-(6-Amino-pyridin-3-yl)-6-oxo-1,7-diaza-spiro[4,4]nonane-1-carboxylicacid tert-butyl ester

Following nitro group reduction procedure 1,(7-(6-nitro-pyridin-3-yl)-6-oxo-1,7-diaza-spiro[4,4]nonane-1-carboxylicacid tert-butyl ester (1.55 g, 4.28 mmol) was converted to7-(6-Amino-pyridin-3-yl)-6-oxo-1,7-diaza-spiro[4,4]nonane-1-carboxylicacid tert-butyl ester (1 g) in 70% yield. 1H NMR (400 MHz, CD₃OD) δ8.21-8.05 (m, 1H), 7.87-7.68 (m, 1H), 6.68-6.57 (m, 1H), 3.85-3.72 (m2H), 3.60-3.40 (m, 2H), 2.67-2.47 (m, 1H), 2.23-1.83 (m, 5H), 1.46 9s,3H), 1.39 (s, 6H). HR-MS m/z 333.1933 (M+H)⁺

Step 3

Preparation of7-(6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl-amino-pyridin-3-yl)-6-oxo-1,7-diaza-spiro[4,4]nonane-1-carboxylicacid tert-butyl ester

Following general N—C coupling procedure 1,7-(6-amino-pyridin-3-yl)-6-oxo-1,7-diaza-spiro[4,4]nonane-1-carboxylicacid tert-butyl ester (114 mg, 0.34 mmol) was combined with2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic aciddimethylamide (100 mg, 0.34 mmol), which after silica gel columnchromatography gave7-(6-(7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl-amino-pyridin-3-yl)-6-oxo-1,7-diaza-spiro[4,4]nonane-1-carboxylicacid tert-butyl ester (100 mg) in 49% yield. MS m/z 589.5 (M+H)⁺

Step 4

Preparation of7-Cyclopentyl-2-[5-(6-oxo-1,7-diaza-spiro[4,4]non-7-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-6-carboxylicacid dimethylamide

Following deprotection method 1,7-(6-(7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl-amino-pyridin-3-yl)-6-oxo-1,7-diaza-spiro[4,4]nonane-1-carboxylicacid tert-butyl ester (100 mg, 0.17 mmol) was converted to7-cyclopentyl-2-[5-(6-oxo-1,7-diaza-spiro[4,4]non-7-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-6-carboxylicacid dimethylamide (80 mg) in 96% yield. ¹H NMR (400 MHz, CD₃OD) δ 8.77(s, 1H), 8.60-8.53 (m, 1H), 8.50-8.42 (m, 1H), 8.18-8.16 (m, 1H), 6.63(s, 1H), 4.83-4.67 (m, 1H), 3.93-3.78 (m 2H), 3.25-3.11 (m, 1H), 3.15(s, 6H), 3.06-2.95 (m, 1H), 2.65-2.46 (m, 2H), 2.32-1.83 (m, 10H),1.83-1.68 (m, 2H). HR-MS m/z 489.2727 (M+H)⁺

Example 114

Step 1

Preparation of2-(6-Nitro-pyridin-3-yl)-1-oxo-2,9-diaza-spiro[5,5]undecane-9-carboxylicacid tert-butyl ester

Following general N—C coupling procedure 1,1-oxo-2,9-diaza-spiro[5,5]undercane-9-carboxylic acid tert-butyl ester(200 mg, 0.74 mmol) in dioxane was combined with 5-bromo-2-nitropyridine(150 mg, 0.74 mmol) which after purification gave2-(6-nitro-pyridin-3-yl)-1-oxo-2,9-diaza-spiro[5,5]undecane-9-carboxylicacid tert-butyl ester (100 mg) in 34% yield. 1H NMR (400 MHz, CD₂Cl₂)8.56 (d, J=2.51 Hz, 1H), δ 8.28 (d, J=8.53 Hz, 1H), 8.03-7.98 (m, 1H),3.91-3.75 (m 4H), 3.29-3.16 (m, 2H), 2.23-1.94 (m, 6H), 1.65-1.55 (m,2H), 1.47 (s, 9H). MS m/z 391.2 (M+H)⁺

Step 2

Preparation of2-(6-Amino-pyridin-3-yl)-1-oxo-2,9-diaza-spiro[5,5]undecane-9-carboxylicacid tert-butyl ester

Following nitro group reduction procedure 1,2-(6-nitro-pyridin-3-yl)-1-oxo-2,9-diaza-spiro[5,5]undecane-9-carboxylicacid tert-butyl ester (100 mg, 0.26 mmol) was converted to2-(6-amino-pyridin-3-yl)-1-oxo-2,9-diaza-spiro[5,5]undecane-9-carboxylicacid tert-butyl ester (92 mg) in 100% yield. 1H NMR (400 MHz, CD₃OD) δ7.75 (d, J=2.51 Hz, 1H), 7.34-7.28 (m, 1H), 6.59 (d, J=9.54 Hz, 1H),3.89-3.74 (m, 3H), 3.67-3.54 (m, 3H), 2.11-1.92 (m, 6H), 1.65-1.52 (m,2H), 1.45 (s, 9H). MS m/z 361.5 (M+H)⁺

Step 3

Preparation of2[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-1-oxo-2,9-diaza-spiro[5,5]undecane-9-carboxylicacid tert-butyl ester

Following general N—C coupling procedure 1,2-(6-amino-pyridin-3-yl)-1-oxo-2,9-diaza-spiro[5,5]undecane-9-carboxylicacid tert-butyl ester (98 mg, 0.27 mmol) was combined with2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic aciddimethylamide (80 mg, 0.27 mmol) which gave2[6-(7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-1-oxo-2,9-diaza-spiro[5,5]undecane-9-carboxylicacid tert-butyl ester (155 mg) in 92% yield. 1H NMR (400 MHz, CD₂Cl₂) δ8.92-8.70 (m, 1H), 8.63-8.53 (m, 1H), 8.25-8.13 (m, 1H), 7.75-7.36 (m,1H), 6.59-6.46 (m, 1H), 4.93-4.70 (m, 1H), 3.93-3.78 (m 2H), 3.74-3.65(m, 2H), 3.28-3.18 (m, 2H), 3.14 (s, 6H), 2.65-2.49 (m, 2H), 2.24-1.88(m, 9H), 1.85-1.71 (m, 2H), 1.65-1.50 (m, 3H), 1.47 (s, 9H); HR-MS m/z617.3583 (M+H)⁺

Step 4

Preparation of7-Cyclopentyl-2-[5-(1-oxo-2,9-diaza-spiro[5,5]undec-2-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Following deprotection method 1,2[6-(7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-1-oxo-2,9-diaza-spiro[5,5]undecane-9-carboxylicacid tert-butyl ester (45 mg, 0.07 mmol) was converted to7-Cyclopentyl-2-[5-(1-oxo-2,9-diaza-spiro[5,5]undec-2-yl)-pyridin-2ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide (30 mg) in 80% yield. 1H NMR (400 MHz, CD₃OD) δ 8.77(s, 1H), 8.51 (d, J=9.03 Hz, 1H), 8.18-8.12 (m, 1H), 7.73-7.64 (m, 1H),6.64 (s, 1H), 4.85-4.71 (m, 1H), 3.74-3.64 (m 2H), 3.15 (s, 6H),3.08-2.96 (m, 2H), 2.92-2.81 (m, 2H), 2.64-2.48 (m, 2H), 2.21-1.98 (m,10H), 1.81-1.69 (m, 2H), 1.68-1.58 (m, 2H). HR-MS m/z 517.3040 (M+H)⁺

Example 115

7-Cyclopentyl-2[5-(1-oxo-hexahydro-pyrrolo[1,2-a]pyrazin-2-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Step 1

Preparation of2-(6-Nitro-pyridin-3-yl)-hexahydro-pyrrolo[1,2-a]pyrazin-1-1one

Following general N—C coupling procedure 1,hexahydro-pyrrolo[1,2-a]pyrazin-1-one was combined with5-bromo-2-nitropyridine which gave2-(6-Nitro-pyridin-3-yl)-hexahydro-pyrrolo[1,2-a]pyrazin-1-1one (250 mg)in 66% yield. ¹H NMR (400 MHz, CD₂Cl₂) δ 8.73 (d, J=2.51 Hz, 1H), 8.37(d, J=8.53 Hz, 1H), 8.29-8.19 (m, 1H), 4.17-4.15 (m 1H), 3.86-3.76 (m,1H), 3.65-3.56 (m, 1H), 3.27-3.02 (m, 3H), 2.89-2.78 (m, 1H), 2.34-2.20(m, 1H), 2.13-1.79 (m, 3H). HR-MS m/z 263.1146 (M+H)⁺.

Step 2

Preparation of2-(6-Amino-pyridin-3-yl)-hexahydro-pyrrolo[1,2-a]pyrazin-1-1one

Following nitro group reduction procedure 12-(6-Nitro-pyridin-3-yl)-hexahydro-pyrrolo[1,2-a]pyrazin-1-1one wasconverted to2-(6-Amino-pyridin-3-yl)-hexahydro-pyrrolo[1,2-a]pyrazin-1-1one (220 mg)in 99% yield. 1H NMR (400 MHz, CD₃OD) δ 8.07-7.78 (m, 1H), 7.65-7.33 (m,1H), 7.06-6.55 (m, 1H), 3.98-3.78 (m 1H), 3.69-3.55 (m, 1H), 3.55-3.44(m, 1H), 3.23-2.96 (m, 3H), 2.87-2.72 (m, 1H), 2.30-2.12 (m, 1H),2.07-1.75 (m, 3H). HR-MS m/z 233.1408 (M+H)⁺

Step 3

Preparation of7-Cyclopentyl-2[5-(1-oxo-hexahydro-pyrrolo[1,2-a]pyrazin-2-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Following general N—C coupling procedure 1,2-(6-Amino-pyridin-3-yl)-hexahydro-pyrrolo[1,2-a]pyrazin-1-1one wascombined with2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic aciddimethylamide which gave7-Cyclopentyl-2[5-(1-oxo-hexahydro-pyrrolo[1,2-a]pyrazin-2-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide (67 mg) in 31% yield. 1H NMR (400 MHz, CD₃OD) δ 8.77(s, 1H), 8.52 (d, J=9.03 Hz, 1H), 8.24 (d, J=2.51 Hz, 1H), 7.76-7.64 (m,1H), 6.64 (s, 1H), 4.84-4.70 (m, 1H), 4.01-3.92 (m, 1H), 3.74-3.64 (m,1H), 3.57-3.51 (m, 1H), 3.16 (s, 6H), 3.25-3.05 (m, 3H), 2.87-2.79 (m,1H), 2.62-2.50 (m, 2H), 2.31-2.22 (m, 1H), 2.16-1.92 (m, 6H), 1.91-1.82(m, 1H), 1.80-1.70 (m, 2H). HR-MS m/z 489.2734 (M+H)⁺

Example 116

7-cyclopentyl-2-(5-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)pyridin-2-ylamino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

Step 1

Preparation of 2-(6-nitro-pyridin-3-yl)-octahydro-pyrrolo[1,2-a]pyrazine

Following general N—C coupling procedure 1,5-bromo-2-nitropyridine (483mg, 2.38 mmole) was combined with octahydropyrrolo[1,2-c]pyrimidine (300mg, 2.38 mmole) which gave2-(6-nitro-pyridin-3-yl)-octahydro-pyrrolo[1,2-a]pyrazine (270 mg) in45% yield. 1H NMR (400 MHz, CD₂Cl₂) δ 8.19-8.09 (m, 2H), 7.26-7.14 (m,1H), 4.05-3.96 (m 1H), 3.92-3.80 (m, 1H), 3.25-3.08 (m, 3H), 2.87-2.74(m, 1H), 2.44-2.32 (m, 1H), 2.28-2.08 (m, 2H), 2.02-1.72 (m, 3H),1.61-1.44 (m, 1H)

MS m/z 249.2 (M+H)⁺

Step 2

Preparation of5-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)pyridin-2-amine

Following nitro group reduction procedure 1,2-(6-Nitro-pyridin-3-yl)-octahydro-pyrrolo[1,2-a]pyrazine (270 mg, 1.09mmole) was converted to5-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)pyridin-2-amine (223 mg) in94% yield. 1H NMR (400 MHz, CD₂Cl₂) δ 7.57 (s, 1H), 7.29 (d, J=9.03 Hz,1H), 6.54 (d, J=9.02 Hz, 1H), 3.50-3.41 (m 1H), 3.36-3.24 (m, 1H),3.13-3.03 (m, 2H), 2.81-2.71 (m, 1H), 2.48-2.34 (m, 2H), 2.30-2.15 (m,2H), 1.95-1.73 (m, 3H), 1.52-1.37 (m, 1H)

HR-MS m/z 219.1612 (M+H)⁺

Step 3

Preparation of7-cyclopentyl-2-(5-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)pyridin-2-ylamino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

Following general N—C coupling procedure 1,2-chloro-7-cyclopentyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide(100 mg, 0.34 mmole) was combined with5-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)pyridin-2-amine (74.6 mg,0.34 mmole) which gave7-cyclopentyl-2-(5-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)pyridin-2-ylamino)-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide(60 mg) in 37% yield. 1H NMR (400 MHz, DMSO) δ 9.30 (s, 1H). 8.77 (s,1H), 8.18-8.12 (m, 1H), 8.02-7.98 (m, 1H), 7.48-7.40 (m, 1H), 6.59 (s,1H), 4.78-4.68 (m, 1H), 3.77-3.72 (m, 1H), 3.62-3.55 (m, 1H), 3.08 (s,3H), 3.04 (s, 3H), 2.77-2.63 (m, 2H), 2.51-2.31 (m, 4H), 2.30-2.21 (m,1H), 2.13-1.91 (m, 6H), 1.88-1.58 (m, 5H), 1.43-1.33 (m, 1H) HR-MS m/z475.2941 (M+H)⁺

Example 117

7-cyclopentyl-N,N-dimethyl-2-(5-(1-oxo-2,8-diazaspiro[4.5]decan-2-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

Step 1

Preparation of tert-butyl2-(6-aminopyridin-3-yl)-3-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate

Following nitro group reduction procedure 1, tert-butyl2-(6-nitropyridin-3-yl)-3-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate(400 mg, 1.06 mmole) was converted to tert-butyl2-(6-aminopyridin-3-yl)-3-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate(250 mg) in 67% yield. 1H NMR (400 MHz, CD₃OD) δ 8.03 (s, 1H), 7.73-7.63(m, 1H), 6.64-6.56 (m, 1H), 3.68 (s, 2H), 3.61-3.48 (m, 2H), 3.45-3.34(m, 2H), 2.51 (s, 2H), 1.73-1.62 (m, 4H), 1.45 (s, 9H); HR-MS m/z347.2092 (M+H)⁺

Step 2

Preparation of2-(6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)pyridin-3-yl)-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate

Following general N—C coupling procedure 1,2-chloro-7-cyclopentyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide(135 mg, 0.46 mmole) was combined with tert-butyl2-(6-aminopyridin-3-yl)-3-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate(160 mg, 0.46 mmole) which gave tert-butyl2-(6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)pyridin-3-yl)-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate(270 mg) in 97% yield. 1H NMR (400 MHz, CD₂Cl₂) δ 8.70 (s, 1H),8.47-8.36 (m, 2H), 8.29 (s, 1H), 8.02-7.94 (m, 1H), 6.38 (s, 1H),4.79-4.66 (m, 1H), 3.58 (s, 2H), 3.54-3.45 (m, 2H), 3.28-3.18 (m, 2H),3.02 (s, 6H), 2.55-2.40 (m, 2H), 2.42 (s, 2H), 2.04-1.90 (m, 4H),1.73-1.49 (m, 6H), 1.36 (s, 9H); HR-MS m/z 603.3406 (M+H)⁺

Step 3

Preparation of7-cyclopentyl-N,N-dimethyl-2-(5-(1-oxo-2,8-diazaspiro[4.5]decan-2-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

Following de protection method 1, tert-Butyl2-(6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)pyridin-3-yl)-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate(270 mg, 0.45 mmole) was converted to7-cyclopentyl-N,N-dimethyl-2-(5-(1-oxo-2,8-diazaspiro[4.5]decan-2-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide(86 mg) in 38% yield. 1H NMR (400 MHz, CD₃OD) δ 8.76 (s, 1H), 8.53-8.50(m, 1H), 8.48-8.42 (m, 1H), 8.11-8.05 (m, 1H), 6.64 (s, 1H), 4.84-4.71(m, 1H), 3.79 (s, 2H), 3.21-3.10 (m, 6H), 2.96-2.82 (m, 4H), 2.62-2.50(m, 4H), 2.16-2.01 (m, 4H), 1.82-1.67 (m, 6H). HR-MS m/z 503.2882 (M+H)⁺

Example 118

7-cyclopentyl-N,N-dimethyl-2-(5-(5′-oxo-8-azaspiro[bicyclo[3.2.1]octane-3,3′-pyrrolidine]-1′-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

Step 1

Preparation of tert-butyl1′-(6-aminopyridin-3-yl)-5′-oxo-8-azaspiro[bicyclo[3.2.1]octane-3,3′-pyrrolidine]-8-carboxylate

Following nitro group reduction procedure 1, tert-Butyl1′-(6-nitropyridin-3-yl)-5′-oxo-8-azaspiro[bicyclo[3.2.1]octane-3,3′-pyrrolidine]-8-carboxylate(400 mg, 0.99 mmole) was converted to tert-butyl1′-(6-aminopyridin-3-yl)-5′-oxo-8-azaspiro[bicyclo[3.2.1]octane-3,3′-pyrrolidine]-8-carboxylate(150 mg) in 40% yield. 1H NMR (400 MHz, CD₃OD) δ 8.01 (s, 1H), 7.69-7.62(m, 1H), 6.63-6.55 (m, 1H), 4.32-4.21 (m, 2H), 3.52 (s, 2H), 2.81 (s,2H), 2.07-1.83 (m, 8H), 1.49 (s, 9H) HR-MS m/z 373.2239 (M+H)⁺

Step 2

Preparation of tert-butyl1′-(6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)pyridin-3-yl)-5′-oxo-8-azaspiro[bicyclo[3.2.1]octane-3,3′-pyrrolidine]-8-carboxylate

Following general N—C coupling procedure 1,2-chloro-7-cyclopentyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide(162 mg, 0.55 mmole) was combined with tert-Butyl1′-(6-aminopyridin-3-yl)-5′-oxo-8-azaspiro[bicyclo[3.2.1]octane-3,3′-pyrrolidine]-8-carboxylate(150 mg, 0.55 mmole) which gave tert-butyl1′-(6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)pyridin-3-yl)-5′-oxo-8-azaspiro[bicyclo[3.2.1]octane-3,3′-pyrrolidine]-8-carboxylate(250 mg) in 86% yield. 1H NMR (400 MHz, CD₂Cl₂) δ 8.76 (s, 1H),8.56-8.49 (m, 1H), 8.41 (s, 1H), 8.08-7.99 (m, 2H), 6.49 (s, 1H),4.88-4.77 (m, 1H), 4.31 (s, 2H), 3.62-3.49 (m, 2H), 3.14 (s, 6H), 2.82(s, 2H), 2.65-2.51 (m, 2H), 2.16-1.53 (m, 14H), 1.49 (s, 9H)

HR-MS m/z 629.3568 (M+H)⁺

Step 3

Preparation of7-cyclopentyl-N,N-dimethyl-2-(5-(5′-oxo-8-azaspiro[bicyclo[3.2.1]octane-3,3′-pyrrolidine]-1′-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

Following general amide formation method 1, tert-Butyl1′-(6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)pyridin-3-yl)-5′-oxo-8-azaspiro[bicyclo[3.2.1]octane-3,3′-pyrrolidine]-8-carboxylate(250 mg, 0.47 mmole) was converted to7-cyclopentyl-N,N-dimethyl-2-(5-(5′-oxo-8-azaspiro[bicyclo[3.2.1]octane-3,3′-pyrrolidine]-1′-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide(56 mg) in 22% yield. 1H NMR (400 MHz, CD₃OD) δ 8.76 (s, 1H), 8.50-8.41(m, 2H), 8.06-8.00 (m, 1H), 6.64 (s, 1H), 4.83-4.72 (m, 1H), 3.73 (br,2H), 3.66 (s, 2H), 3.16 (s, 6H), 2.82 (s, 2H), 2.64-2.49 (m, 2H),2.16-1.89 (m, 12H), 1.83-1.69 (m, 2H). HR-MS m/z 529.3035 (M+H)⁺

Example 119

7-cyclopentyl-N,N-dimethyl-2-(5-(2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

Step 1

Preparation of tert-butyl3-(6-nitropyridin-3-yl)-2-oxo-1-oxa-3,8-diazaspiro[4.5]decane-8-carboxylateester

Following general N—C coupling procedure 1,5-bromo-2-nitropyridine (238mg, 1.17 mmole) was combined with tert-butyl2-oxo-1-oxa-3,8-diazaspiro[4.5]decane-8-carboxylate (300 mg, 1.17 mmole)which gave tert-butyl3-(6-nitropyridin-3-yl)-2-oxo-1-oxa-3,8-diazaspiro[4.5]decane-8-carboxylateester (400 mg) in 90% yield.

1H NMR (400 MHz, CD₂Cl₂) δ 8.66 (s, 1H), 8.51-8.44 (m, 1H), 8.37-8.31(m, 1H), 4.00-3.86 (m, 1H), 3.74-3.65 (m, 1H), 3.44-3.28 (m, 2H),3.22-3.08 (m, 2H), 2.08-1.99 (m, 2H), 1.93-1.81 (m, 2H), 1.49 (s, 9H).MS m/z 379.1616 (M+H)⁺

Step 2

Preparation of tert-butyl3-(6-aminopyridin-3-yl)-2-oxo-1-oxa-3,8-diazaspiro[4.5]decane-8-carboxylate

Following nitro group reduction procedure 1, tert-Butyl3-(6-nitropyridin-3-yl)-2-oxo-1-oxa-3,8-diazaspiro[4.5]decane-8-carboxylateester (400 mg, 1.06 mmole) was converted to tert-butyl3-(6-aminopyridin-3-yl)-2-oxo-1-oxa-3,8-diazaspiro[4.5]decane-8-carboxylate(370 mg) in 100% yield. 1H NMR (400 MHz, CD₃OD) δ 8.00 (s, 1H), 7.77 (d,J=9.03 Hz, 1H), 6.64 (d, J=9.03 Hz, 1H), 3.88-3.75 (m, 2H), 3.44-3.33(m, 2H), 3.31 (s, 2H), 2.01-1.93 (m, 2H), 1.89-1.78 (m, 2H), 1.46 (s,9H). MS m/z 349.1879 (M+H)⁺

Step 3

Preparation of tert-butyl3-(6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)pyridin-3-yl)-2-oxo-1-oxa-3,8-diazaspiro[4.5]decane-8-carboxylate

Following general N—C coupling procedure 1,2-chloro-7-cyclopentyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide(133 mg, 0.45 mmole) was combined with tert-butyl3-(6-aminopyridin-3-yl)-2-oxo-1-oxa-3,8-diazaspiro[4.5]decane-8-carboxylate(158 mg. 0.45 mmole) which gave tert-butyl3-(6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)pyridin-3-yl)-2-oxo-1-oxa-3,8-diazaspiro[4.5]decane-8-carboxylate (170mg) in 62% yield. 1H NMR (400 MHz, CD₂Cl₂) δ 8.89 (s, 1H), 8.76 (s, 1H),8.46 (d, J=9.03 Hz, 1H), 8.38 (d, J=2.51 Hz, 1H), 7.97-7.92 (m, 1H),6.40 (s, 1H), 4.78-4.68 (m, 1H), 3.83-3.73 (m, 2H), 3.71 (s, 2H),3.33-3.21 (m, 2H), 3.02 (s, 6H), 2.54-2.40 (m, 2H), 2.05-1.86 (m, 6H),1.78-1.58 (m, 4H), 1.38 (s, 9H) HR-MS m/z 605.3221 (M+H)⁺

Step 4

Preparation of7-cyclopentyl-N,N-dimethyl-2-(5-(2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

Following deprotection method 1,tert-Butyl3-(6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)pyridin-3-yl)-2-oxo-1-oxa-3,8-diazaspiro[4.5]decane-8-carboxylate (150mg, 0.25 mmole) was converted to7-cyclopentyl-N,N-dimethyl-2-(5-(2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-3-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide(170 mg) in 62% yield.

1H NMR (400 MHz, DMSO) δ 9.72 (s, 1H), 8.80 (s, 1H), 8.49-8.43 (m, 1H),8.37-8.31 (m, 1H), 8.05-8.00 (m, 1H), 6.40 (s, 1H), 4.81-4.67 (m, 1H),3.91 (s, 2H), 3.35-3.30 (m, 1H), 3.07 (s, 3H), 3.04 (s, 3H), 2.91-2.79(m, 2H), 2.75-2.64 (m, 2H), 2.55-2.36 (m, 2H), 2.09-1.90 (m, 4H),1.83-1.73 (m, 4H), 1.72-1.59 (m, 2H)

HR-MS m/z 505.2694 (M+H)⁺

Example 120

N,N-dimethyl-2-(5-(5′-oxo-8-azaspiro[bicyclo[3.2.1]octane-3,3′-pyrrolidine]-1′-yl)pyridin-2-ylamino)-7-(tetrahydro-2H-pyran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

Step 1

Preparation of tert-butyl1′-(6-(6-(dimethylcarbamoyl)-7-(tetrahydro-2H-pyran-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)pyridin-3-yl)-5′-oxo-8-azaspiro[bicyclo[3.2.1]octane-3,3′-pyrrolidine]-8-carboxylate

Following general N—C coupling procedure 1,2-chloro-N,N-dimethyl-7-(tetrahydro-2H-pyran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide(70.6 mg, 0.23 mmole) was combined with tert-butyl1′-(6-aminopyridin-3-yl)-5′-oxo-8-azaspiro[bicyclo[3.2.1]octane-3,3′-pyrrolidine]-8-carboxylate(62 mg, 0.23 mmole) which gave tert-butyl(dimethylcarbamoyl)-7-(tetrahydro-2H-pyran-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)pyridin-3-yl)-5′-oxo-8-azaspiro[bicyclo[3.2.1]octane-3,3′-pyrrolidine]-8-carboxylate(71 mg) in 57% yield. 1H NMR (400 MHz, CD₂Cl₂) δ 8.77 (s, 1H), 8.65-8.57(m, 1H), 8.49 (m, 1H), 8.15-8.08 (m, 1H), 6.56 (s, 1H), 4.63-4.52 (m,1H), 4.30 (br, 2H), 4.08-3.96 (m, 2H), 3.64-3.51 (m, 3H), 3.18 (S, 6H),2.96-2.86 (m, 1 H), 2.83 (s, 2H), 2.16-1.99 (m, 3H), 1.96-1.79 (m, 5H),1.77-1.52 (m, 4H), 1.51 (s, 9H). HR-MS m/z 645.3527 (M+H)⁺

Step 2

Preparation ofN,N-dimethyl-2-(5-(5′-oxo-8-azaspiro[bicyclo[3.2.1]octane-3,3′-pyrrolidine]-1′-yl)pyridin-2-ylamino)-7-(tetrahydro-2H-pyran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

Following deprotection method 1, tert-Butyl1′-(6-(6-(dimethylcarbamoyl)-7-(tetrahydro-2H-pyran-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)pyridin-3-yl)-5′-oxo-8-azaspiro[bicyclo[3.2.1]octane-3,3′-pyrrolidine]-8-carboxylate(68 mg, 0.125 mmole) was converted toN,N-dimethyl-2-(5-(5′-oxo-8-azaspiro[bicyclo[3.2.1]octane-3,3′-pyrrolidine]-1′-yl)pyridin-2-ylamino)-7-(tetrahydro-2H-pyran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide(17 mg) in 25% yield. 1H NMR (400 MHz, CD₃OD) δ 8.77 (s, 1H), 8.52-8.46(m, 2H), 8.08-8.03 (m, 1H), 6.68 (s, 1H), 4.57-4.39 (m, 1H), 4.04-3.96(m, 2H), 3.65 (s, 2H), 3.64-3.46 (m, 3H), 3.20 (s, 3H), 3.15 (s, 3H),2.94-2.84 (m, 1H), 2.83 (s, 2H), 2.14-2.04 (m, 1H), 1.98-1.77 (m, 11H).HR-MS m/z 545.2991 (M+H)⁺

Example 121

N,N-dimethyl-2-(5-(6-oxo-1,7-diazaspiro[4.4]nonan-7-yl)pyridin-2-ylamino)-7-(tetrahydro-2H-pyran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

Step 1

Preparation of tert-butyl7-(6-(6-(dimethylcarbamoyl)-7-(tetrahydro-2H-pyran-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)pyridin-3-yl)-6-oxo-1,7-diazaspiro[4.4]nonane-1-carboxylate

Following general N—C coupling procedure 1,2-chloro-N,N-dimethyl-7-(tetrahydro-2H-pyran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide(76 mg, 0.246 mmole) was combined with tert-butyl7-(6-aminopyridin-3-yl)-6-oxo-1,7-diazaspiro[4.4]nonane-1-carboxylate(82 mg, 0.246 mmole) which gave tert-butyl7-(6-(6-(dimethylcarbamoyl)-7-(tetrahydro-2H-pyran-3-yl)-7H-pyrrolo[2,3-c]pyrimidin-2-ylamino)pyridin-3-yl)-6-oxo-1,7-diazaspiro[4.4]nonane-1-carboxylate(107 mg) in 72% yield. 1H NMR (400 MHz, CD₂Cl₂) δ 8.80 (s, 1H),8.69-8.57 (m, 2H), 8.35-8.25 (m, 1H), 6.54 (s, 1H), 4.63-4.52 (m, 1H),4.06-3.88 (m, 2H), 3.86-3.70 (m, 2H), 3.64-3.46 (m, 2H), 3.18 (S, 6H),3.02-2.84 (m, 1H), 2.84-2.59 (m, 1H), 2.24-1.99 (m, 6H), 1.96-1.79 (m,3H), 1.77-1.52 (m, 1H), 1.48 (s, 4H), 1.39 (s, 5H). HR-MS m/z 605.3210(M+H)⁺

Step 2

Preparation ofN,N-dimethyl-2-(5-(6-oxo-1,7-diazaspiro[4.4]nonan-7-yl)pyridin-2-ylamino)-7-(tetrahydro-2H-pyran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

Following deprotection method 1, tert-Butyl7-(6-(6-(dimethylcarbamoyl)-7-(tetrahydro-2H-pyran-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)pyridin-3-yl)-6-oxo-1,7-diazaspiro[4.4]nonane-1-carboxylate(100 mg, 0.165 mmole) was converted toN,N-dimethyl-2-(5-(6-oxo-1,7-diazaspiro[4.4]nonan-7-yl)pyridin-2-ylamino)-7-(tetrahydro-2H-pyran-3-yl)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide(62 mg) in 74% yield. 1H NMR (400 MHz, CD₃OD) δ 8.76 (s, 1H), 8.58-8.56(m, 1H), 8.53 (s, 1H), 8.50 (s, 1H), 8.20-8.14 (m, 1H), 4.57-4.42 (m,2H), 4.04-3.93 (m, 2H), 3.90-3.83 (m, 2H), 3.61-3.51 (m, 1H), 3.49-3.46(m, 1H), 3.21 (S, 3H), 3.16 (s, 3H), 3.03-2.96 (m, 1H), 2.93-2.84 (m,1H), 2.24-2.14 (m, 2H), 2.13-1.77 (m, 7H). HR-MS m/z 505.2693 (M+H)⁺

Example 122

7-Cyclopentyl-2-[5-(4-oxo-3,9-diaza-bicyclo[4.2.1]non-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Step 1

Preparation of 4-Oxo-3,9-diaza-bicyclo[4.2.1]nonane-9-carboxylic acidtert-butyl ester

To a 500 ml Parr shaker bottle was added 10.53 grams (45.7 mmoles) ofracemic 9-Benzyl-3,9-diaza-bicyclo[4.2.1]nonan-4-one 100 mls of methanoland 20 mls of tetrahydrofuran. In a single portion, 11 g (50.4 mmoles)of di-tertbutyl di-carbonate was added. The mixture was then put undernitrogen and about 0.5 grams of 10% palladium on carbon was added. Theresultant mixture was hydrogenated with shaking at about 50 psi hydrogenfor 36 hours. The mixture was removed from the Parr shaker and about 100mls of dichloromethane and 25 grams of celite was added and stirred. Themixture was filtered through a pad of celite, The pad was washed withexcess dichloromethane. The organics were combined and concentrated to athick residue which solidified under vacuum. The solid wasre-crystallized from dichloromethane/heptanes, the white solid was driedunder vacuum which gave4-Oxo-3,9-diaza-bicyclo[4.2.1]nonane-9-carboxylic acid tert-butyl ester10.63 grams in 98% yield.

MS m/z 241 (M+H)⁺.

Step 2

Preparation of 3-(6-Nitro-pyridin-3-yl)-4-oxo-3,9-diazabicyclo[4.2.1]nonane-9-carboxylic acid tert-butyl ester

Following general N—C coupling procedure 1,4-Oxo-3,9-diaza-bicyclo[4.2.1]nonane-9-carboxylic acid tert-butyl ester,1.86 g (7.72 mmoles) was combined with 5-Bromo-2-nitro-pyridine, 1.51 g(7.42 mmoles), which after recrystallized from CH₂Cl₂-Heptanes gave3-(6-Nitro-pyridin-3-yl)-4-oxo-3,9-diazabicyclo[4.2.1]nonane-9-carboxylic acid tea-butyl ester, (1.59 g) in 58%yield. TLC Rf ˜0.45 (75% Ethyl acetate-Heptane)

MS m/z 363 (M+H)⁺

Step 3

Preparation of3-(6-Amino-pyridin-3-yl)-4-oxo-3,9-diaza-bicyclo[4.2.1]nonane-9-carboxylicacid tert-butyl ester

Following nitro group reduction procedure 13-(6-Nitro-pyridin-3-yl)-4-oxo-3,9-diazabicyclo[4.2.1]nonane-9-carboxylic acid tert-butyl ester 1.59 grams (4.24mmoles) was converted to3-(6-Amino-pyridin-3-yl)-4-oxo-3,9-diaza-bicyclo[4.2.1]nonane-9-carboxylicacid tert-butyl ester (1.41 grams) in 98% yield.

MS m/z 333 (M+H)⁺.

Step 4

Preparation of3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-4-oxo-3,9-diaza-bicyclo[4.2.1]nonane-9-carboxylicacid tert-butyl ester

Following general Scheme 5 on a 1.023 mmole scale,3-(6-Amino-pyridin-3-yl)-4-oxo-3,9-diaza-bicyclo[4.2.1]nonane-9-carboxylicacid tert-butyl ester was combined with2-chloro-7-cyclopentyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamidewhich yielded after SiO₂ gel Chromatograped (5-8% CH₃OH-ethyl acetate),0.57 grams (95% yield) of3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-4-oxo-3,9-diaza-bicyclo[4.2.1]nonane-9-carboxylicacid tert-butyl ester, TLC RF 0.4 in 5% CH₃OH-ethyl acetate, MS m/z 589(M+H)⁺

Step 5

Preparation of7-Cyclopentyl-2-[5-(4-oxo-3,9-diaza-bicyclo[4.2.1]non-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide di-hydrochloride salt

To 0.55 grams (0.96 mmoles) of3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-4-oxo-3,9-diaza-bicyclo[4.2.1]nonane-9-carboxylicacid tert-butyl ester was added 15 ml of ethyl acetate. The mixture wasstirred at room temperature under N₂ and cooled to ice bath temperature.To this mixture was added 5 mls 4N HCl in dioxane. The resultant mixturewas allowed to stir until all starting material was consumed. Theresultant mixture was stirred until all starting material was consumedas determined by HPLC-MS. To this mixture was added 50 ml of a 1:1mixture of ethyl acetate/diethyl ether to precipitate solids. The solidswere filtered and washed with excess 1:1 mixture of ethylacetate/diethyl ether and dried under vacuum to a constant weight toyield7-Cyclopentyl-2-[5-(4-oxo-3,9-diaza-bicyclo[4.2.1]non-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide as the di-hydrochloride salt, 0.213 grams (45%yield). MS m/z 489 (M+H)⁺. ¹H NMR (400 MHz, D6 DMSO) δ 10.2 (s, 1H,broad), 9.05 (s, 1H, broad), 8.35 (s, 1H), 8.0 (d, 1H), 7.7 (d, 1H), 6.9(s, 1H), 4.82 (m, 1H, broad), 4.6 (d, 1H), 4.25 (s, 1H, broad), 4.15 (s,1H, broad), 3.82 (m, 1H, broad), 3.5 (d, 1H), 3.05 (s, 6H), 2.82 (m,1H), 2.3 (m, 2H), 2.2-1.95 (m, 10H, broad), 1.89 (m, 1H), 1.65 (m, 2H).

Example 123 Preparation of7-Cyclopentyl-2-[5-((1R,6S)-4-oxo-3,9-diaza-bicyclo[4.2.1]non-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Chiral Separation of racemic7-Cyclopentyl-2-[5-(4-oxo-3,9-diaza-bicyclo[4.2.1]non-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide (235 mg) gave approximately equal amounts of the plusand minus enantiomer.

7-Cyclopentyl-2-[5-((1R,6S)-4-oxo-3,9-diaza-bicyclo[4.2.1]non-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide. MS m/z 489 (M+H)⁺

¹H NMR (400 MHz, D6 DMSO) δ 10.2 (s, 1H, broad), 9.05 (s, 1H, broad),8.35 (s, 1H), 8.0 (d, 1H), 7.7 (d, 1H), 6.9 (s, 1H), 4.82 (m, 1H,broad), 4.6 (d, 1H), 4.25 (s, 1H, broad), 4.15 (s, 1H, broad), 3.82 (m,1H), 3.5 (d, 1H), 3.05 (s, 6H), 2.82 (m, 1H), 2.3 (m, 2H), 2.2-1.95 (m,10H, broad), 1.89 (m, 1H), 1.65 (m, 2H)

Example 123

7-Cyclopentyl-2-[5-((1R,6S)-4-oxo-3,9-diaza-bicyclo[4.2.1]non-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Step 1

Preparation of3-(6-Nitro-pyridin-3-yl)-4-oxo-3,9-diaza-bicyclo[4.2.1]nonane-9-carboxylicacid tert-butyl ester

Following general N—C coupling procedure 1,5-Bromo-2-nitropyridine (1gm, 4.93 mmol) was combined with tert-butyl4-oxo-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate (1.18 gm, 4.93 mmol)which gave tert-butyl3-(6-nitropyridin-3-yl)-4-oxo-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate(1.4 gm) in 78% yield.

Step 2

Separation of 1 gm of the racemate3-(6-Nitro-pyridin-3-yl)-4-oxo-3,9-diaza-bicyclo[4.2.1]nonane-9-carboxylicacid tert-butyl ester using the following conditions: 20×250 mm 5 umprep IA column with a mobile phase of 30% MeOH/70% CO₂ gaveapproximately 320 mg of (1S,6R)-tert-butyl3-(6-nitropyridin-3-yl)-4-oxo-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate.MS m/z 363.4 (M+H)

Enantiomer 2, (1R,6S)-tert-butyl3-(6-nitropyridin-3-yl)-4-oxo-3,9-diazabicyclo[4.2.1]nonane-9-carboxylateand (1S,6R)-tert-butyl3-(6-nitropyridin-3-yl)-4-oxo-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate(320 mg). MS m/z 363.4 (M+H)

Step 3

Preparation of(1R,6S)-3-(6-Amino-pyridin-3-yl)-4-oxo-3,9-diazabicyclo[4.2.1]nonane-9-carboxylicacid tert-butyl ester

Following nitro group reduction procedure 1, (1R,6S)-tert-butyl3-(6-nitropyridin-3-yl)-4-oxo-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate(360 mg, 0.96 mmol) was converted to(1R,6S)-3-(6-amino-pyridin-3-yl)-4-oxo-3,9-diaza-bicyclo[4.2.1]nonane-9-carboxylicacid tert-butyl ester (293 mg) in 92% yield

MS m/z 332.9 (M+H)

Step 4

Preparation of (1R,6S)-tert-butyl3-(6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)pyridin-3-yl)-4-oxo-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate

Following general N—C coupling procedure 1,(1R,6S)-3-(6-Amino-pyridin-3-yl)-4-oxo-3,9-diaza-bicyclo[4.2.1]nonane-9-carboxylicacid tert-butyl ester (0.548 gm, 1.65 mmol) was combined with2-chloro-7-cyclopentyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide(483 mg, 1.65 mmol) which gave (1R,6S)-tert-butyl3-(6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)pyridin-3-yl)-4-oxo-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate(858 mg) in 88% yield.

MS m/z 588.7 (M+H)

Step 5

Preparation of7-Cyclopentyl-2-[5-((1R,6S)-4-oxo-3,9-diaza-bicyclo[4.2.1]non-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Following deprotection method 1, (1R,6S)-tert-butyl3-(6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)pyridin-3-yl)-4-oxo-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate(858 mg, 1.46 mmol) was converted to7-cyclopentyl-2-[5-((1R,6S)-4-oxo-3,9-diaza-bicyclo[4.2.1]non-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide (700 mg) in 98% yield.

MS m/z 488.7 (M+H)⁺.

Example 124

7-Cyclopentyl-2-[5-((1S,6R)-4-oxo-3,9-diaza-bicyclo[4.2.1]non-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide was prepared from the chiral separation of racematefrom example 122 to what has been done before.

¹H NMR (400 MHz, D6 DMSO) δ 10.2 (s, 1H, broad), 9.05 (s, 1H, broad),8.35 (s, 1H), 8.0 (d, 1H), 7.7 (d, 1H), 6.9 (s, 1H), 4.82 (m, 1H,broad), 4.6 (d, 1H), 4.25 (s, 1H, broad), 4.15 (s, 1H, broad), 3.82 (m,1H), 3.5 (d, 1H), 3.05 (s, 6H), 2.82 (m, 1H), 2.3 (m, 2H), 2.2-1.95 (m,10H, broad), 1.89 (m, 1H), 1.65 (m, 2H)

MS m/z 489 (M+H)⁺

Example 125

7-cyclopentyl-2-[5-((1R,6S)-9-methyl-4-oxo-3,9-diaza-bicyclo[4.2.1]non-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-c]pyrimidine-6-carboxylicacid methylamide

Step 1

Preparation of(1R,6S)-3-[6-(7-Cyclopentyl-6-methylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-4-oxo-3,9-diaza-bicyclo[4.2.1]nonane-9-carboxylicacid tert-butyl ester

Following general N—C coupling procedure 1,2-chloro-7-cyclopentyl-N-methyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamidewas combined with (1R,6S)-tert-butyl3-(6-aminopyridin-3-yl)-4-oxo-3,9-diazabicyclo[4.2.1]nonane-9-carboxylatewhich gave(1R,6S)-3-[6-(7-cyclopentyl-6-methylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl])-4-oxo-3,9-diaza-bicyclo[4.2.1]nonane-9-carboxylicacid tert-butyl ester (200 mg) in 78% yield. MS 575.8 m/z (M+H)

Step 2

Preparation of7-Cyclopentyl-2-[5-((1R,6S)-4-oxo-3,9-diaza-bicyclo[4.2.1]non-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid methylamide

Following deprotection method 1,(1R,6S)-3-[6-(7-Cyclopentyl-6-methylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-4-oxo-3,9-diaza-bicyclo[4.2.1]nonane-9-carboxylicacid tert-butyl ester was converted to7-cyclopentyl-2-[5-((1R,6S)-4-oxo-3,9-diaza-bicyclo[4.2.1]non-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacidmethylamide (550 mg) in 52% yield. MS 475.6 m/z (M+H)

Step 3

Preparation of7-Cyclopentyl-2-[5-((1R,6S)-9-methyl-4-oxo-3,9-diaza-bicyclo[4.2.1]non-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid methylamide

Following general reductive alkylation method1,7-cyclopentyl-2-[5-((1R,6S)-4-oxo-3,9-diaza-bicyclo[4.2.1]non-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid methylamide was combined with formaldehyde which gave7-cyclopentyl-2-[5-((1R,65)-9-methyl-4-oxo-3,9-diaza-bicyclo[4.2.1]non-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid methylamide (100 mg) in 98% yield.

1H NMR (400 MHz, CDCl₃-d) δ ppm 8.75 (s, 1H), 8.49 (d, J=9.09 Hz, 1H),8.21 (s, 1H), 8.16 (d, J=2.53 Hz, 1H), 7.53 (dd, J=8.84, 2.78 Hz, 1H),6.66 (s, 1H), 6.21 (d, J=4.55 Hz, 1H), 5.48 (t, J=8.84 Hz, 1H), 4.22 (d,J=14.65 Hz, 1H), 3.41 (m, 1H), 3.32 (ddd, J=17.43, 6.57, 6.32 Hz, 2H),3.01 (d, J=5.05 Hz, 6H), 2.76 (dd, J=15.66, 7.07 Hz, 1H), 2.59 (m, 2H),2.45 (s, 3H), 2.20 (m, 2H), 2.06 (br. s., 4H), 1.94 (m, 2H)

MS 489.1 m/z (M+H)

Example 126

7-Cyclohexyl-2-[6-(3,8-diaza-bicyclo[3.2.1]oct-3-yl)-pyridazin-3-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Step 1

Preparation of3-(6-Amino-pyridazin-3-yl)-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester

In a mortar and pestle 6-chloro-pyridazin-3-ylamine (100 mg, 0.772 mmol)and 3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester(180 mg, 0.849 mmol) were grounded together, placed in a sealed tube andheated to 130° C. for 16 h. The reaction was allowed to cool to roomtemperature and then the contents were dissolved in a minimal amount ofdichloromethane. The crude product was purified by silica gelchromatography using a 0-50% ethyl acetate heptane gradient which gave3-(6-amino-pyridazin-3-yl)-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester (70.7 mg, 0.232 mmol) in 30% yield.

MS m/z 306.1 (M+H)⁺.

Step 2

Preparation of3-[6-(7-Cyclohexyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridazin-3-yl]-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester

Following general N—C coupling procedure 1,2-chloro-7-cyclohexyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic aciddimethylamide (25.2 mg, 0.082 mmol), was combined with3-(6-amino-pyridazin-3-yl)-3,8-diaza-bicyclo[3.2.1] which after silicagel purification (0-10% methano ethyl acetate gradient) gave3-[6-(7-cyclohexyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridazin-3-yl]-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester (25 mg, 0.043 mmol) in. MS m/z 576.3 (M+H)⁺.

Step 3

Preparation of7-Cyclohexyl-2-[6-(3,8-diaza-bicyclo[3.2.1]oct-3-yl)-pyridazin-3-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Following deprotection method 2,3-[6-(7-cyclohexyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridazin-3-yl]-3,8-diaza-bicyclo[3.2.1]octane-8-carboxylicacid tert-butyl ester (25 mg, 0.043 mmol) was converted to7-cyclohexyl-2-[6-(3,8-diaza-bicyclo[3.2.1]oct-3-yl)-pyridazin-3-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide (18 mg, 0.038 mmol) in 88% yield. 1H NMR (400 MHz,DMSO-d₆) δ ppm 9.66 (m, 1H), 8.74 (s, 1H), 8.21 (d, J=9.60 Hz, 1H), 7.21(d, J=10.11 Hz, 1H), 6.59 (s, 1H), 4.23 (m, 1H), 3.81 (m, 2H), 3.52 (br.s., 2H), 3.05 (br. s., 6H), 2.92 (m, 2H), 2.42 (m, 2H), 1.82 (t, J=13.39Hz, 5H), 1.67 (m, 5H), 1.27 (m, 3H).

MS m/z 476.2 (M+H)⁺.

Example 127

7-(4-(2-cyanopropan-2-yl)phenyl)-N,N-dimethyl-2-(5-(4-oxo-3,9-diazabicyclo[4.2.1]nonan-3-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

Step 1

Preparation of tert-butyl3-(6-(7-(4-(2-cyanopropan-2-yl)phenyl)-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)pyridin-3-yl)-4-oxo-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate

Following general N—C coupling procedure 1,3-(6-Amino-pyridin-3-yl)-4-oxo-3,9-diaza-bicyclo[4.2.1]nonane-9-carboxylicacid tert-butyl ester was combined with2-Chloro-7-[4-(cyano-dimethyl-methyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide which gave tert-butyl3-(6-(7-(4-(2-cyanopropan-2-yl)phenyl)-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)pyridin-3-yl)-4-oxo-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate(160 mg) in 89% yield. MS m/z 664.7

Step 2

Preparation of7-(4-(2-cyanopropan-2-yl)phenyl)-N,N-dimethyl-2-(5-(4-oxo-3,9-diazabicyclo[4.2.1]nonan-3-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

Following deprotection method 1, tert-butyl3-(6-(7-(4-(2-cyanopropan-2-yl)phenyl)-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)pyridin-3-yl)-4-oxo-3,9-diazabicyclo[4.2.1]nonane-9-carboxylatewas converted to7-(4-(2-cyanopropan-2-yl)phenyl)-N,N-dimethyl-2-(5-(4-oxo-3,9-diazabicyclo[4.2.1]nonan-3-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide(72 mg) in 53% yield. 1H NMR (400 MHz, DMSO-d₆) δ ppm 9.91 (br. s., 1H),9.63 (br. s., 2H), 8.94 (s, 1H), 8.23 (d, J=8.59 Hz, 1H), 8.16 (br. s.,1H), 7.72 (d, J=8.59 Hz, 1H), 7.54 (m, 1H), 6.95 (s, 1H), 4.40 (d,J=16.17 Hz, 1H), 4.16 (m, 2H), 3.73 (dd, J=16.17, 6.57 Hz, 1H), 3.31 (m,3H), 3.02 (m, 6H), 2.80 (dd, J=16.67, 7.58 Hz, 1H), 2.08 (m, 3H), 1.89(br. s., 1H), 1.77 (s, 6H).

MS m/z 546.0 (M+H)

Example 128

2-[5-(4-oxo-3,9-diaza-bicyclo[4.2.1]non-3-yl)-pyridin-2-ylamino]-7-phenyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Step 1

Preparation of3-[6-(6-Dimethylcarbamoyl-7-phenyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-4-oxo-3,9-diaza-bicyclo[4.2.1]nonane-9-carboxylicacid tert-butyl ester

Following general N—C coupling procedure 1,2-chloro-7-phenyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic aciddimethylamide (181 mg, 0.602 mmol) was combined with3-(6-amino-pyridin-3-yl)-4-oxo-3,9-diaza-bicyclo[4.2.1]nonane-9-carboxylicacid tert-butyl ester (200 mg, 0.602 mmol), which gave3-[6-(6-dimethylcarbamoyl-7-phenyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-4-oxo-3,9-diaza-bicyclo[4.2.1]nonane-9-carboxylicacid tert-butyl ester (320 mg, 0.536 mmol) in 86% yield.

MS m/z 597.6 (M+H)⁺.

Step 2

Preparation of2-[5-(4-oxo-3,9-diaza-bicyclo[4.2.1]non-3-yl)-pyridin-2-ylamino]-7-phenyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Following deprotection method 1,3-[6-(6-dimethylcarbamoyl-7-phenyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-4-oxo-3,9-diaza-bicyclo[4.2.1]nonane-9-carboxylicacid tert-butyl ester (320 mg, 0.536 mmol) was converted to thehydrochloride salt of2-[5-(4-oxo-3,9-diaza-bicyclo[4.2.1]non-3-yl)-pyridin-2-ylamino]-7-phenyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide (200 mg, 0.403 mmol). 1H NMR (400 MHz, DMSO-d₆) δ ppm9.74 (m, 2H), 9.02 (s, 1H), 8.22 (d, J=2.53 Hz, 1H), 8.05 (d, J=8.08 Hz,1H), 7.70 (d, J=7.58 Hz, 1H), 7.58 (t, J=7.83 Hz, 2H), 7.48 (m, 3H),6.99 (s, 1H), 4.44 (d, J=16.17 Hz, 1H), 4.22 (br. s., 2H), 3.76 (dd,J=16.17, 6.57 Hz, 1H), 3.57 (s, 0H), 2.91 (m, 8H), 2.10 (m, 3H), 1.90(m, 1H).

MS m/z 496.8 (M+H)⁺.

Step 3.

The enantiomers of2-[5-(4-oxo-3,9-diaza-bicyclo[4.2.1]non-3-yl)-pyridin-2-ylamino]-7-phenyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide were separated using chiral chromatography (AD-Hcolumn, 21×250 mm column, 40% isopropyl alcohol with 0.2%diethylamine/60% CO₂) which gave the following.

Example 129

2-[5-((1S,6R)-4-Oxo-3,9-diaza-bicyclo[4.2.1]non-3-yl)-pyridin-2-ylamino]-7-phenyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

1H NMR (400 MHz, DMSO-d₆) δ ppm 9.74 (m, 2H), 9.02 (s, 1H), 8.22 (d,J=2.53 Hz, 1H), 8.05 (d, J=8.08 Hz, 1H), 7.70 (d, J=7.58 Hz, 1H), 7.58(t, J=7.83 Hz, 2H), 7.48 (m, 3H), 6.99 (s, 1H), 4.44 (d, J=16.17 Hz,1H), 4.22 (br. s., 2H), 3.76 (dd, J=16.17, 6.57 Hz, 1H), 3.57 (s, 0H),2.91 (m, 8H), 2.10 (m, 3H), 1.90 (m, 1H). MS m/z 497 (M+H)⁺. Retentiontime of 1.88

Example 130

2-[5-((1R,6S)-4-Oxo-3,9-diaza-bicyclo[4.2.1]non-3-yl)-pyridin-2-ylamino]-7-phenyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide. 1H NMR (400 MHz, DMSO-d₆) δ ppm 9.74 (m, 2H), 9.02(s, 1H), 8.22 (d, J=2.53 Hz, 1H), 8.05 (d, J=8.08 Hz, 1H), 7.70 (d,J=7.58 Hz, 1H), 7.58 (t, J=7.83 Hz, 2H), 7.48 (m, 3H), 6.99 (s, 1H),4.44 (d, J=16.17 Hz, 1H), 4.22 (br. s., 2H), 3.76 (dd, J=16.17, 6.57 Hz,1H), 3.57 (s, 0H), 2.91 (m, 8H), 2.10 (m, 3H), 1.90 (m, 1H). MS m/z 497(M+H)^(#). Retention time of 2.61 minutes.

Example 131

7-cyclohexyl-N,N-dimethyl-2-(5-(4-oxo-3,9-diazabicyclo[4.2.1]nonan-3-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

Step 1

Preparation of tert-butyl3-(6-(7-cyclohexyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)pyridin-3-yl)-4-oxo-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate

Following general N—C coupling procedure 1, tert-butyl3-(6-aminopyridin-3-yl)-4-oxo-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate(120 mg, 0.361 mmol) was combined with2-chloro-7-cyclohexyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide(111 mg, 0.361 mmol) which gave tert-butyl3-(6-(7-cyclohexyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)pyridin-3-yl)-4-oxo-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate(120 mg) in 55.1% yield. MS m/z 603.6 (M+H)⁺.

Step 2

Preparation of7-cyclohexyl-N,N-dimethyl-2-(5-(4-oxo-3,9-diazabicyclo[4.2.1]nonan-3-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

Following deprotection method 1, tert-butyl3-(6-(7-cyclohexyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)pyridin-3-yl)-4-oxo-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate(120 mg, 0.199 mmol) was converted to the hydrochloride salt of7-cyclohexyl-N,N-dimethyl-2-(5-(4-oxo-3,9-diazabicyclo[4.2.1]nonan-3-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide(90 mg) in 90% yield. 1H NMR (400 MHz, CDCl₃) δ ppm 8.75 (s, 1H), 8.63(d, J=9.03 Hz, 1H), 8.18 (d, J=2.51 Hz, 2H), 7.58 (d, J=7.53 Hz, 1H),6.47 (s, 1H), 4.37 (t, J=3.51 Hz, 1H), 4.13 (d, J=14.56 Hz, 1H), 3.75(m, 2H), 3.62 (dd, J=14.56, 6.53 Hz, 1H), 3.18 (s, 6H), 2.97 (m, 2H),2.63 (d, J=11.04 Hz, 2H), 2.03 (m, 7H), 1.82 (d, J=11.54 Hz, 2H), 1.40(m, 4H).

MS m/z 502.9 (M+H)⁺.

Example 132

7-Cyclohexyl-2-[5-((1S,6R)-4-oxo-3,9-diaza-bicyclo[4.2.1]non-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Enantiomers were separated using chiral chromatography (AD-H column,21×250 mm column, 40% isopropyl alcohol with 0.2% diethylamine 160% CO₂:Enantiomer 1 had a retention time of 1.75 minutes and

Example 133

7-Cyclohexyl-2-[5-((1R,6S)-4-oxo-3,9-diaza-bicyclo[4.2.1]non-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Enantiomer 2 had a retention time of 2.21 minutes.

Example 134

7-Cyclobutyl-2-[5-(4-oxo-3,9-diaza-bicyclo[4.2.1]non-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Step 1

Preparation of tert-butyl3-(6-(7-cyclobutyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)pyridin-3-yl)-4-oxo-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate

Following general N—C coupling procedure 1,tert-butyl-3-(6-aminopyridin-3-yl)-4-oxo-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate(119 mg, 0.359 mmol) was combined with2-chloro-7-cyclobutyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide(100 mg, 0.359 mmol) which gave tert-butyl3-(6-(7-cyclobutyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)pyridin-3-yl)-4-oxo-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate(150 mg) in 73% yield. MS m/z 575.2 (M+H)⁺.

Step 2

Preparation of7-Cyclobutyl-2-[5-(4-oxo-3,9-diaza-bicyclo[4.2.1]non-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Following deprotection method 1, tert-butyl3-(6-(7-cyclobutyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)pyridin-3-yl)-4-oxo-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate(153 mg, 0.266 mmol) was converted to the HCl salt of7-Cyclobutyl-2-[5-(4-oxo-3,9-diaza-bicyclo[4.2.1]non-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide (76 mg) in 60% yield. 1H NMR (400 MHz, CDCl₃-d) δ ppm8.75 (s, 1H), 8.63 (d, J=9.09 Hz, 1H), 8.17 (m, 2H), 7.59 (dd, J=8.59,2.53 Hz, 1H), 6.47 (s, 1H), 5.00 (t, J=8.59 Hz, 1H), 4.12 (d, J=14.65Hz, 1H), 3.75 (m, 2H), 3.62 (dd, J=14.91, 6.32 Hz, 1H), 3.24 (dd, 2H),3.17 (s, 6H), 2.94 (m, 2H), 2.50 (m, 2H), 1.98 (m, 7H). MS m/z 475.4(M+H)⁺.

Example 135

7-Cyclobutyl-2-[5-((1S,6R)-4-oxo-3,9-diaza-bicyclo[4.2.1]non-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Using chiral chromatography (IA column, 21×250 mm column, 40% isopropylalcohol with 0.2% diethylamine/60% CO₂, the enantiomers of7-Cyclobutyl-2-[5-(4-oxo-3,9-diaza-bicyclo[4.2.1]non-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide were separated.

Enantiomer1,7-Cyclobutyl-2-[5-((1S,6R)-4-oxo-3,9-diaza-bicyclo[4.2.1]non-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide, had a retention time of 1.98 minutes. 1H NMR (400MHz, CDCl₃-d) δ ppm 8.75 (s, 1H), 8.63 (d, J=9.09 Hz, 1H), 8.17 (m, 2H),7.59 (dd, J=8.59, 2.53 Hz, 1H), 6.47 (s, 1H), 5.00 (t, J=8.59 Hz, 1H),4.12 (d, J=14.65 Hz, 1H), 3.75 (m, 2H), 3.62 (dd, J=14.91, 6.32 Hz, 1H),3.24 (dd, 2H), 3.17 (s, 6H), 2.94 (m, 2H), 2.50 (m, 2H), 1.98 (m, 7H).MS m/z 475.4 (M+H)⁺.

Example 136

7-Cyclobutyl-2-[5-((1R,6S)-4-oxo-3,9-diaza-bicyclo[4.2.1]non-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Enantiomer2,7-Cyclobutyl-2-[5-((1R,6S)-4-oxo-3,9-diaza-bicyclo[4.2.1]non-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide, had a retention time of 2.72 minutes. 1H NMR (400MHz, CDCl₃-d) δ ppm 8.75 (s, 1H), 8.63 (d, J=9.09 Hz, 1H), 8.17 (m, 2H),7.59 (dd, J=8.59, 2.53 Hz, 1H), 6.47 (s, 1H), 5.00 (1, J=8.59 Hz, 1H),4.12 (d, J=14.65 Hz, 1H), 3.75 (m, 2H), 3.62 (dd, J=14.91, 6.32 Hz, 1H),3.24 (dd, 2H), 3.17 (s, 6H), 2.94 (m, 2H), 2.50 (m, 2H), 1.98 (m, 7H).

MS m/z 475.4 (M+H)⁺.

Example 137

7-cyclopentyl-N,N-dimethyl-2-(5-((1S,6R)-9-(methylsulfonyl)-4-oxo-3,9-diazabicyclo[4.2.1]nonan-3-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

Preparation of7-cyclopentyl-N,N-dimethyl-2-(5-((1S,6R)-9-(methylsulfonyl)-4-oxo-3,9-diazabicyclo[4.2.1]nonan-3-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

A sample of7-Cyclopentyl-N,N-dimethyl-2-(5-((1S,6R)-4-oxo-3,9-diazabicyclo[4.2.1]nonan-3-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide(50 mg, 0.102 mmol), methanesulfonyl chloride (12.3 mg, 0.107 mmol) anddiisopropyl ethylamine (0.027 ml, 0.154 mmol) were combined into 1 mlDCM in a crew cap vial along with a stir bar and allowed to stir for 16hr. The reaction was then taken up into EtOAc, and extracted withsaturated Na₂CO₃ solution, then with brine and the organic layer driedover Na₂SO₄. The crude product was purified by normal phasechromatography (0-75% ethyl acetate in Heptane) which gave7-cyclopentyl-N,N-dimethyl-2-(5-((1S,6R)-9-(methylsulfonyl)-4-oxo-3,9-diazabicyclo[4.2.1]nonan-3-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide(25 mg) in 44% yield. 1H NMR (400 MHz, CDCl₃) δ ppm 8.66 (s, 2H), 8.47(d, J=9.09 Hz, 2H), 8.07 (d, J=2.53 Hz, 1H), 7.46 (m, 1H), 6.40 (s, 1H),4.73 (m, 1H), 4.42 (m, 1H), 4.31 (m, 1H), 4.20 (d, 1H), 3.64 (s, 2H),3.09 (s, 6H), 3.00 (d, J=4.04 Hz, 1H), 2.90 (s, 3H), 2.49 (m, 2H), 2.00(m, 4H), 1.66 (br. s., 4H). MS m/z 566.9 (M+H).

Example 138

2-(5-((1S,6R)-9-(2-acetamidoacetyl)-4-oxo-3,9-diazabicyclo[4.2.1]nonan-3-yl)pyridin-2-ylamino)-7-cyclopentyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

Preparation of2-(5-((1S,6R)-9-(2-acetamidoacetyl)-4-oxo-3,9-diazabicyclo[4.2.1]nonan-3-yl)pyridin-2-ylamino)-7-cyclopentyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

2-Acetamidoacetic acid (12 mg, 0.102 mmol) was combined withdiisopropylethylamine (0.018 ml, 0.102 mmol) and HBTU (38.8 mg, 0.102mmol) in DMF (1 ml) for 15 min.7-Cyclopentyl-N,N-dimethyl-2-(5-((1S,6R)-4-oxo-3,9-diazabicyclo[4.2.1]nonan-3-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide(50 mg, 0.102 mmol) was then added and the reaction allowed to stir for4 hrs. The reaction was then poured into brine and extracted with ethylacetate. The combined ethyl acetate extracts were dried with sodiumsulfate, filtered, concentrated and the resulting residue purified bysilica gel chromatography which gave2-(5-((1S,6R)-9-(2-acetamidoacetyl)-4-oxo-3,9-diazabicyclo[4.2.1]nonan-3-yl)pyridin-2-ylamino)-7-cyclopentyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide(45 mg) in 77% yield. 1H NMR (400 MHz, DMSO-d₆) δ ppm 9.71 (d, J=8.08Hz, 2H), 8.82 (s, 1H), 8.14 (d, J=2.53 Hz, 1H), 8.07 (d, J=6.06 Hz, 1H),7.61 (d, J=9.09 Hz, 2H), 6.63 (s, 2H), 4.76 (m, 2H), 4.53 (br. s., 1H),4.44 (br. s., 0H), 4.21 (d, J=14.65 Hz, 0H), 3.95 (m, 2H), 3.61 (dd,J=14.91, 5.81 Hz, 1H), 3.04 (m, 6H), 2.78 (m, 1H), 2.40 (m, 3H), 2.00(m, 6H), 1.89 (s, 3H), 1.66 (m, 3H). MS m/z 588.6 (M+H)

Example 139

2-(5-((1S,6R)-9-acetyl-4-oxo-3,9-diazabicyclo[4.2.1]nonan-3-yl)pyridin-2-ylamino)-7-cyclopentyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

Preparation of2-(5-((1S,6R)-9-acetyl-4-oxo-3,9-diazabicyclo[4.2.1]nonan-3-yl)pyridin-2-ylamino)-7-cyclopentyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

A sample of7-Cyclopentyl-N,N-dimethyl-2-(5-((1S,6R)-4-oxo-3,9-diazabicyclo[4.2.1]nonan-3-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide(50 mg, 0.102 mmol), acetic anhydride (0.020 ml, 0.113 mmol) anddiisopropylethylamine (0.014 ml, 0.154 mmol) were combined with 1 mlDCM. The mixture was allowed to stir for 16 hr and then taken up intoEtOAc, washed with brine, dried over Na₂SO₄ filtered and concentrated.The crude product was purified by silica gel chromatography which gave2-(5-((1S,6R)-9-acetyl-4-oxo-3,9-diazabicyclo[4.2.1]nonan-3-yl)pyridin-2-ylamino)-7-cyclopentyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide(32 mg) 52% yield. 1H NMR (400 MHz, DMSO-d₆) δ ppm 9.70 (d, J=8.08 Hz,1H), 8.82 (s, 1H), 8.33 (dd, J=9.09, 6.06 Hz, 1H), 8.13 (d, J=2.53 Hz,1H), 7.60 (dd, J=9.09, 2.53 Hz, 1H), 6.63 (s, 1H), 4.76 (t, J=8.84 Hz,1H), 4.70 (br. s., 0H), 4.55 (m, 0H), 4.43 (s, 0H), 4.34 (br. s., 0H),4.18 (d, J=14.65 Hz, 0H), 4.06 (d, J=14.15 Hz, 0H), 3.59 (m, 1H), 3.06(br. s., 6H), 2.98 (d, J=16.17 Hz, 1H), 2.87 (d, J=14.65 Hz, 0H), 2.73(m, 1H), 2.44 (br. s., 2H), 2.19 (m, 1H), 2.05 (d, J=4.55 Hz, 3H), 1.98(m, 6H), 1.82 (m, 2H), 1.66 (d, J=5.56 Hz, 3H), 1.23 (br. s., 1H). MSm/z 531.6 (M+H).

Example 140

7-cyclopentyl-N,N-dimethyl-2-(5-((1R,6S)-9-methyl-4-oxo-3,9-diazabicyclo[4.2.1]nonan-3-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

Preparation of7-cyclopentyl-N,N-dimethyl-2-(5-((1R,6S)-9-methyl-4-oxo-3,9-diazabicyclo[4.2.1]nonan-3-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

Following general reductive alkylation method1,7-cyclopentyl-N,N-dimethyl-2-(5-((1R,6S)-4-oxo-3,9-diazabicyclo[4.2.1]nonan-3-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide(90 mg, 0.184 mmol) was combined with formaldehyde (37% solution inwater, 0.041 ml, 1.474 mmol) which after silica gel chromatography gave7-cyclopentyl-N,N-dimethyl-2-(5-((1R,6S)-9-methyl-4-oxo-3,9-diazabicyclo[4.2.1]nonan-3-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide(90 mg) in 97% yield. 1H NMR (400 MHz, DMSO-d₆) δ ppm 9.69 (s, 1H), 8.81(s, 1H), 8.31 (d, J=9.09 Hz, 1H), 8.12 (d, J=2.53 Hz, 1H), 7.58 (dd,J=9.09, 2.53 Hz, 1H), 6.63 (s, 1H), 4.76 (m, 1H), 4.16 (d, J=14.65 Hz,1H), 3.35 (m, 1H), 3.28 (m, 1H), 3.20 (t, J=6.57 Hz, 1H), 3.06 (br. s.,6H), 2.99 (m, 1H), 2.46 (m, 2H), 2.34 (s, 3H), 2.06 (m, 6H), 1.81 (m,2H), 1.67 (m, 3H). MS m/z 503.6 (M+H)⁺.

Example 141

7-Cyclopentyl-2-[5-((1S,6R)-9-methyl-4-oxo-3,9-diaza-bicyclo[4.2.1]non-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Preparation of7-Cyclopentyl-2-[5-((1S,6R)-9-methyl-4-oxo-3,9-diaza-bicyclo[4.2.1]non-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Following general reductive alkylation method1,7-Cyclopentyl-2-[5-((1S,6R)-4-oxo-3,9-diaza-bicyclo[4.2.1]non-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide was combined with formaldehyde (37% solution inwater) which after purification gave7-cyclopentyl-2-[5-((1S,6R)-9-methyl-4-oxo-3,9-diaza-bicyclo[4.2.1]non-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide (41 mg) in 80% yield. 1H NMR (400 MHz, DMSO-d₆) δ ppm9.69 (s, 1H), 8.81 (s, 1H), 8.31 (d, J=9.09 Hz, 1H), 8.12 (d, J=2.53 Hz,1H), 7.58 (dd, J=9.09, 2.53 Hz, 1H), 6.63 (s, 1H), 4.76 (m, 1H), 4.16(d, J=14.65 Hz, 1H), 3.35 (m, 1H), 3.28 (m, 1H), 3.20 (t, J=6.57 Hz,1H), 3.06 (br. s., 6H), 2.99 (m, 1H), 2.46 (m, 2H), 2.34 (s, 3H), 2.06(m, 6H), 1.81 (m, 2H), 1.67 (m, 3H).

MS m/z 502.9 (M+H)⁺.

Example 142

7-Cyclopentyl-2-[5-((1S,6R)-9-isopropyl-4-oxo-3,9-diaza-bicyclo[4.2.1]non-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Preparation of7-Cyclopentyl-2-[5-((1S,6R)-9-isopropyl-4-oxo-3,9-diaza-bicyclo[4.2.1]non-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Following general reductive alkylation method1,7-Cyclopentyl-N,N-dimethyl-2-(5-((1S,6R)-4-oxo-3,9-diazabicyclo[4.2.1]nonan-3-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide(65 mg, 0.133 mmol) was combined with acetone (0.05 mL, 0.665 mmol)which gave7-cyclopentyl-2-[5-((1S,6R)-9-isopropyl-4-oxo-3,9-diaza-bicyclo[4.2.1]non-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide (61 mg) in 86% yield. 1H NMR (400 MHz, CHLOROFORM-d)δ ppm 8.67 (s, 1H), 8.44 (d, J=8.59 Hz, 1H), 8.12 (s, 1H), 8.08 (d,J=2.53 Hz, 1H), 7.46 (dd, J=8.59, 2.53 Hz, 1H), 6.38 (s, 1H), 4.73 (t,J=9.09 Hz, 1H), 4.24 (d, J=14.65 Hz, 1H), 3.59 (m, 2H), 3.21 (br. s.,1H), 3.08 (m, 7H), 2.97 (br. s., 1H), 2.53 (m, 3H), 1.95 (m, 6H), 1.66(m, 3H), 1.07 (t, J=5.81 Hz, 6H).

MS m/z 531.6 (M+H)

Example 143

7-Cyclopentyl-2-[5-((1S,6R)-9-trideuteromethyl-4-oxo-3,9-diazabicyclo[4.2.1]non-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Preparation of7-Cyclopentyl-2-[5-((1S,6R)-9-trideuteromethyl-4-oxo-3,9-diazabicyclo[4.2.1]non-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Following general reductive alkylation method1,7-Cyclopentyl-N,N-dimethyl-2-(5-((1S,6R)-4-oxo-3,9-diazabicyclo[4.2.1]nonan-3-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide(50 mg, 0.102 mmol) was combined with formaldehyde-d₂ (0.015 ml, 0.015mL) which gave7-cyclopentyl-2-[5-a1S,6R)-9-trideuteromethyl-4-oxo-3,9-diazabicyclo[4.2.1]non-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide (43 mg) in 85% yield. 1H NMR (400 MHz, CDCl₃) δ ppm8.75 (s, 1H), 8.53 (d, J=9.09 Hz, 1H), 8.16 (m, 1H), 7.56 (dd, J=9.09,2.53 Hz, 1H), 6.48 (s, 1H), 4.82 (t, J=8.84 Hz, 1H), 4.26 (m, 1H), 3.41(m, 6H), 3.16 (m, 2H), 2.79 (m, 3H), 2.59 (m, 2H), 2.24 (br. s., 2H),2.08 (m, 6H), 1.75 (m, 3H). MS m/z 506.6 (M+H)

Example 144

7-cyclopentyl-N,N-dimethyl-2-(5-((1R,6S)-4-oxo-9-(2,2,2-trifluoroethyl)-3,9-diazabicyclo[4.2.1]nonan-3-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

Preparation of7-cyclopentyl-N,N-dimethyl-2-(5-((1R,6S)-4-oxo-9-(2,2,2-trifluoroethyl)-3,9-diazabicyclo[4.2.1]nonan-3-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide

A sample of7-Cyclopentyl-N,N-dimethyl-2-(5-((1S,6R)-4-oxo-3,9-diazabicyclo[4.2.1]nonan-3-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide(60 mg, 0.123 mmol) was combined with 2,2,2-trifluoroethyltrifluoromethanesulfonate (0.035 ml, 0.246 mmol) in dimethylformamide (1mL) and heated to (80° C.) overnight. The reaction was then poured intowater and extracted with ethyl acetate. The aqueous was washed withethyl acetate. The organics were combined, dried over sodium sulfate,filtered and concentrated which gave a crude material that was purifiedby silica gel column chromatography which gave7-cyclopentyl-N,N-dimethyl-2-(5-((1R,6S)-4-oxo-9-(2,2,2-trifluoroethyl)-3,9-diazabicyclo[4.2.1]nonan-3-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide(45 mg) in 64% yield. 1H NMR (400 MHz, CDCl₃) δ ppm 8.74 (s, 1H), 8.51(d, J=9.09 Hz, 1H), 8.22 (s, 1H), 8.15 (d, J=2.53 Hz, 1H), 7.52 (dd,J=8.84, 2.78 Hz, 1H), 6.46 (s, 1H), 4.80 (t, J=8.59 Hz, 1H), 4.23 (d,J=13.64 Hz, 1H), 3.47 (m, 3H), 3.16 (s, 6H), 3.06 (m, 3H), 2.83 (dd,J=15.66, 7.07 Hz, 1H), 2.57 (dd, J=12.13, 8.59 Hz, 2H), 2.04 (m, 6H),1.70 (m, 4H). MS m/z 571.6 (M+H)

Example 145

7-Cyclopentyl-2-[5-(4-oxo-8-oxa-3,10-diaza-bicyclo[4.3.1]dec-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Step 1

Preparation of3-(6-Nitro-pyridin-3-yl)-4-oxo-8-oxa-3,10-diaza-bicyclo[4.3.1]decane-10-carboxylicacid tert-butyl ester

Following general N—C coupling procedure 1,4-Oxo-8-oxa-3,10-diaza-bicyclo[4.3.1]decane-10-carboxylic acidtert-butyl ester (0.776 g, 3.03 mmol) was combined with5-Bromo-2-nitro-pyridine (0.676 g, 3.33 mmol) which gave3-(6-Nitro-pyridin-3-yl)-4-oxo-8-oxa-3,10-diaza-bicyclo[4.3.1]decane-10-carboxylicacid tert-butyl ester (0.69 g, 1.732) in 57.2 yield. MS m/z 379.4 (M+H)

Step 2

Preparation of3-(6-Amino-pyridin-3-yl)-4-oxo-8-oxa-3,10-diaza-bicyclo[4.3.1]decane-10-carboxylicacid tert-butyl ester

Following general nitro reduction procedure3-(6-niro-pyridin-3-yl)-4-oxo-8-oxa-3,10-diaza-bicyclo[4.3.1]decane-10-carboxylicacid tert-butyl ester (690 mg, 1.824 mmol) was converted to3-(6-Amino-pyridin-3-yl)-4-oxo-8-oxa-3,10-diaza-bicyclo[4.3.1]decane-10-carboxylicacid tert-butyl ester (351 mg, 1.007 mmol) in 55.2% yield.

MS m/z 349.3 (M+H)

Step 3

Preparation of3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-4-oxo-8-oxa-3,10-diaza-bicyclo[4.3.1]decane-10-carboxylicacid tert-butyl ester

Following general N—C coupling procedure 1,3-(6-Amino-pyridin-3-yl)-4-oxo-8-oxa-3,10-diaza-bicyclo[4.3.1]decane-10-carboxylicacid tert-butyl ester (350 mg, 1.047 mmol) was combined with2-Chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic aciddimethylamide (337 mg, 1.151 mmol) which gave3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-4-oxo-8-oxa-3,10-diaza-bicyclo[4.3.1]decane-10-carboxylicacid tert-butyl ester (476 mg, 0.787 mmol) in 75% yield.

MS m/z 604.6 (M+H)

Step 4

Preparation of7-Cyclopentyl-2-[5-(4-oxo-8-oxa-3,10-diaza-bicyclo[4.3.1]dec-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

Following deprotection method 1,3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-4-oxo-8-oxa-3,10-diaza-bicyclo[4.3.1]decane-10-carboxylicacid tert-butyl ester (470 mg, 0.777 mmol) was converted to7-Cyclopentyl-2-[5-(4-oxo-8-oxa-3,10-diaza-bicyclo[4.3.1]dec-3-0)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide (231 mg, 0.457 mmol) in 58.8% yield. ¹H NMR (400 MHz,D6 DMSO) δ 10.2 (s, 1H, broad), 9.05 (s, 1H, broad), 8.35 (s, 1H), 8.0(d, 1H), 7.7 (d, 1H), 6.9 (s, 1H), 4.82 (m, 1H, broad), 4.6 (d, 1H),4.25 (s, 1H, broad), 4.15 (s, 1H, broad), 3.82 (m, 1H, broad), 3.5 (d,1H), 3.05 (s, 6H), 2.82 (m, 1H), 2.3 (m, 2H), 2.2-1.95 (m, 10H, broad),1.89 (m, 1H), 1.65 (m, 2H) MS m/z 504.6 (M+H)

Example 146-147

A sample of7-Cyclopentyl-2[5-(1-oxo-hexahydro-pyrrolo[1,2-a]pyrazin-2-0)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide was chirally separated to give (enantiomer 1)7-Cyclohexyl-2-[5-((S)-1-oxo-hexahydro-pyrrolo[1,2-a]pyrazin-2-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide and (enantiomer 2)7-Cyclohexyl-2-[5-((R)-1-oxo-hexahydro-pyrrolo[1,2-a]pyrazin-2-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide.

Example 146

7-Cyclohexyl-2-[5-((S)-1-oxo-hexahydro-pyrrolo[1,2-a]pyrazin-2-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

White Solid (4 mg) MS m/z 489.3 (M+H)⁺.

Example 147

7-Cyclohexyl-2-[5-((R)-1-oxo-hexahydro-pyrrolo[1,2-a]pyrazin-2-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide

White Solid (5 mg) MS m/z 489.3 (M+H)⁺.

Biological Assays

CDK4/Cyctin D1 Enzymatic Activity Assay

An assay for monitoring CDK4/cyclin D1-catalyzed phosphorylation of pRbat the Ser780 site was performed using TR-FRET in a 384-well format, andwas used for IC₅₀ determination and kinetic analysis. The reaction wascarried out in a 30 μL volume containing 0.3 nM CDK4/cyclin D1, 150 nMbiotin-pRb (773-924), 3 μM ATP, and 1.3% DMSO (or compound in DMSO) inthe assay buffer (50 mM HEPES-Na, pH 7.5; 5 mM MgCl₂, 1 mM DTT, 0.02%Tween-20, and 0.05% BSA). 3 μM ATP was added last to initiate thereaction. The reaction was quenched with 10 μL of 240 mM EDTA-Na (pH8.0) after 60 min incubation at 22° C. The signal was developed by theaddition of 40 μL detection solution containing 40 nM SA-APC, 143 ng/mLanti-phospho-pRb (S780) antibody, and 1 nM Eu-W1024 anti-rabbit IgGantibody in the detection buffer (50 mM HEPES-Na, pH 7.5, 60 mM EDTA-Na,pH 8.0, 0.05% BSA, and 0.1% Triton X-100). After 60 min incubation inthe dark, the plate was read on Envision (Perkin Elmer 2102-0010).

Human CDK4/cyclin D1 was expressed in Sf21 cells via baculovirusinfection.

A CDK6/cyclin D3 enzymatic activity assay can be performed using thegeneral procedures outlined in the CDK4/cyclin D1 enzymatic assay.CDK6/cyclin D3 enzyme complex can be purchased from a commercial source(CarnaBiosciences, Cat. No. 04-107)

CDK1/Cyclin B Enzymatic Activity Assay

A 384-well microtiter IMAP-FP™ (Molecular Devices Trade Mark Technology)endpoint assay was used for CDK1/cyclin B kinase activity measurements.The same assay was used for IC₅₀ determination of small molecueinhibitors. In general, the kinase reactions were carried out in 20 μLvolumes in the reaction solution, which is composed of 2 μL compound (in20% DMSO), 8 μL CDK1/cyclin B in the 1× Reaction Buffer (MolecularDevices, Cat. No. R8139), 10 μL substrate mixture of Tamra Histone-H1peptide (Molecular Devices, Cat. No. R7384) and ATP (Amersham Pharmacia,Cat. No. 27-2056-01) in the 1× Reaction Buffer with 1 mM DTT freshlyadded. The final reaction mixture contains compound (inhibitor) with theconcentration varying from 0.005-10 μM, 2% DMSO, 0.25 nM CDK1/cyclin B,100 nM Tamra Histone-H1 peptide, and 20 μM ATP.

All reactions were run at room temperature in black 384-well flat-bottomCostar plates (Corning, Cat. No. 3710) for 120 min then were quenched bythe addition of 60 μL 400-fold diluted 1× Progressive Binding Buffer A(Molecular Devices, Cat. No. R8139). The fluorescent polarizationsignals were read on the Evision Multilabel Reader (Perkin Elmer,Envision 2102-0010) after 2-hour incubation at room temperature. Note:IC₅₀<0.005 nM or IC₅₀>10 μM indicates the true IC₅₀ is out of detectionrange.

CDK4 Cellular Assays

Cell-based assay measuring phosphorylation levels of pRb at the Ser780site using an enzyme-linked immunosorbent assay (ELISA) method (Table6). JeKo-1, a mantle-cell lymphoma cell line, was selected for use inthis assay due to its known translocation and subsequent overexpressionof cyclin D1. [Ref: Amin, H. M.; McDonnell, T. J.; Medeiros, L. J.;Rassidakis, G. Z.; Leventaki, V.; O'Connor, S. L.; Keating, M. J.; Lai,R. Characterization of 4 mantle cell lymphoma cell lines—Establishmentof an in vitro study model. Arch. Pathol. Lab. Med. 2003, 127, 424-431].

The pRb expressing JeKo-1 mantle cell lymphoma cell line was grown incomplete media consisting of RPMI1640 (Gibco catalog no. 22400-071), 20%FBS (Gibco catalog no. 10082-131), 2 mM L-glutamine (Gibco catalog no.25030-081), and 1% Penicillin/Streptomycin (Gibco catalog no.15140-133). JeKo-1 cells were seeded in Biocoat Cell EnvironmentPoly-D-Lysine 96-well tissue culture plates (Becton Dickinson catalogno. 356461) at 20,000 cells/well in 100 μL final volume of completemedia. Cells were allowed to adhere overnight. Compounds were preparedas 10 mM stock solution in DMSO and diluted to a concentration of 110 μMin complete media in a 96 well tissue culture plate, and then seriallydiluted four fold, allowing a titration curve of 7 points with a finalconcentration of 26 nM. 10 μL of the dilution were then transferred tothe cell culture plate, resulting in a final concentration range of 10μM to 2 nM. The incubation was carried out at 37° C. with 5% CO₂. Allcompounds were tested in triplicates at each concentration. Followingcompound incubation, the media was removed and the cells were lysed in35 μL of lysis buffer, consisting of 50 mM Tris.Cl, pH 7.2, 120 mM NaCl,1 mM EDTA, 6 mM EGTA, 1% NP-40, complete protease inhibitor cocktail(Roche, catalog no. 11836170001) and a protease inhibitor cocktail fromCalbiochem (catalog no. 524525). The plates were placed at 4° C. withvigorous shaking for 5 min to lyse the cells. The resulting lysatescontained approximately 1 μg/μL of protein.

The 4H1 total pRb antibody from Cell signaling technology (catalog no.9309) was added to clear MaxiSorp plates (Nunc catalog no. 442404) at aconcentration of 50 ng per well in 50 μL Dulbecco's Phosphate BufferedSaline (DPBS) (Gibco catalog no. 14190-144). Plates were incubatedovernight at 4° C. with rocking. After a 250 μL wash with TBST (Teknovacatalog no. T9501) and blot-drying, 250 μL Superblock (Pierce catalogno. 37535) was added to each well. After shaking for 10 minutes, theSuperblock solution was replaced with fresh Superblock and plates wereincubated on a shaker for an additional 50 min. After blocking, 30 μL ofJeKo-1 cell lysate, containing approximately 10 μg total protein, wereadded to wells in triplicate. 20 μL PBS (Gibco catalog no. 10010-023)containing 10% Superblock (Pierce catalog no. 37535) were added to eachwell for a final reaction volume of 50 μL. Plates were then sealed withUniseal plate sealers (Whatman catalog no. 7704-0007), and incubated for2 h at room temperature on a shaker. Plates were washed with 3×250 μLTBST. 50 μL of a 1:1000 dilution of anti-phospho Rb Ser⁷⁸⁰ from CellSignaling (catalog no. 9307) in PBS/10% Superblock were added and theplate was incubated on a shaker for 1 h at room temperature. For allincubation steps, plates were covered with Uniseal plate sealers.Following incubation, plates were washed with 3×250 μL TBST. Next, 50 μLof a 1:2500 dilution of donkey-anti-rabbit HRP (Promega catalog no.W401B) in PBS/10% Superblock were added, and plates were incubated for30 min at room temperature on a shaker. Plates were again washed asdescribed above. Finally, 50 μL Ultra TMB ELISA (Pierce catalog no.34028) were added and plates incubated, unsealed, 5-15 min in the dark,until blue color developed. After incubation, 50 μL 2 M sulfuric acidwere added to plates to top the reaction, and absorbance was determinedon a SpectraMax (Molecular Devices, Sunnydale, Calif.) within 15 minutesat 450 nm. All washes were performed using a Bio-Tek plate washer.

The Total Rb ELISA kit (Invitrogen catalog no. KH00011) was used todetermine the levels of total pRb. This kit uses wells precoated with aproprietary total pRb antibody for capture. All reagents listed, withthe exception of cell lysate, were included in the kit. The nature ofthe antibodies used for capture and detection was labeled as proprietaryand not disclosed. 10 μg of cell lysate was loaded into the wells andvolume adjusted to 50 μL with standard dilution buffer. Plates weresealed with film included in the kit and incubated for 2 h at roomtemperature on a shaker. Plates are then manually washed three timeswith 250 μL wash buffer. 50 μL of proprietary primary antibody(pre-conjugated to biotin) was added to wells and incubated for 1 h atroom temperature on a shaker. Then plates were again washed as notedabove. The secondary antibody (HRP pre-conjugated to Streptavidin) wasdiluted 1:100 in Streptavidin-HRP diluent buffer and 50 μL was added toeach well. Plates were then incubated for 30 min. Afterwards, plateswere washed four times with buffer as outlined above. Finally, 50 μLstabilized Chromogen was added per well and plates were incubated for 15min, at which point 50 μL of stop solution was added. Plates were thenread on a Spectramax at 450 nm.

Upon quantitation of the pRb phosphorylation (p-pRb) levels, %inhibition values were derived for each concentration tested and used todetermine 50% inhibitory concentrations (IC₅₀) for a particular compound(non-normalized). The total pRb levels were then used to adjust thep-pRb % inhibition values to account for any loss of signal due to theabsence of the pRb protein itself, and the IC₅₀ values obtained from theadjusted % inhibitions represent normalized cellular p-pRb IC₅₀.

Automated Electrophysiology Studies (Q-Patch Clamp Assay)

Cell cultures: CHO cells constitutively expressing functional hERGchannels were purchased from AVIVA Biosciences Corp. (San Diego,Calif.). Cells were grown in DMEM/F12 (Gibco Cat #11039-021),supplemented with 10% FBS (Gibco Cat #10082-142), 1%Penicillin-Streptomycin (Gibco Cat #15140-122) and 1% Geneticin (GibcoCat #10131-027). Cells were split when they reach-70-90% confluence byaspirating the medium from the culture and rinsing the cell monolayerwith Dulbecco's PBS (Gibco Cat #14190-136). After removing the rinsebuffer, trypsin/EDTA (0.05%, Gibco Cat #25300-054) was added to coverthe cell monolayer and incubated for 1 minute at room temperature.Aspirate the trypsin/EDTA and leave the cells for 1 more minute.Dislodge cells from the flask by tapping the flask. Add complete mediumand pipette up and down several times to mix and dissociate cell clumpsuntil cells were separated. Count the cells and re-seed cells in flasksin 37° C., 5.0% CO2, 100% humidity incubator for passaging cells and 30°C., 5.0% CO2, 100% humidity for compound screening. Before QPatch assay,growth media was removed from the culture flasks, and cells were gentlyrinsed with 12 ml D-PBS once. The cells were immersed in 10 mlTrypsin/EDTA (prepared freshly from 10× frozen stock with D-PBS) at roomtemperature for approximately 30 seconds before the solution wasaspirated, then incubated for 3-4 min at 37° C. At the end theincubation, visibly rounded cells were easily dislodged from the bottomof the flask without any tap. QPatch modified storage media (CHO-S-SFMII, 25 mM HEPES, and 0.04 mg/ml soy bean trypsin inhibitor) was addedand the cells were re-suspended gently by pipetting up and down 6-10times. Cell density and viability were determined with Beckman ViceII.The cell density was adjusted to 2−3×106/ml in QPatch modified storagemedia. The cell suspension was applied to the storage container onQPatch platform immediately.

Solutions and Drugs: Cells were centrifuged (150 g, 2 min), thesupernatant was removed, and the cell pellet was washed twice andfinally resuspended in an extracellular solution (Na-Ringer) containingthe following (in mM): 145 NaCl, 4 KCl, 2CaCl2, 1MgCl2, 10 HEPESadjusted to pH 7.4. Aliquots (300 ul) of this suspension (3-10 3 106cells/ml) were transferred to the chip. The intracellular solutionconsisted of the following (in mM): 120 KCl, 5.374 CaCl2, 1.75 MgCl2, 10KOH/EGTA, 10 HEPES, 5 K2-ATP adjusted to pH 7.2. Amitriptyline(reference control) was from Sigma. All compounds were prepared at 10 mMin 100% DMSO. Each concentration was made by five-fold serial dilutionin 100% DMSO, in a 96-well plate in triplicate. Each dilution was thentransferred and further diluted 333-fold (testing concentration: 0.2 to30 μM) in extracellular solution in a 96-well glass coated plate. Thefinal DMSO concentration was ≦0.3%.

Electrophysiology: All electrophysiological experiments were conductedon a single-channel QPatch test version. The Q-plate has 16 recordingchambers and each chamber has a patch clamp amplifier operating inparallel. The amplifiers are controlled by a custom-made Digital SignalProcessor (DSP) board by Sophion, which performs voltage clamp of asingle cell in whole-cell mode. In the hERG assay the acquisition rateof the whole-cell current during voltage protocol execution was 10 kHz.This current signal was digitally filtered with a cut-off frequency of 3kHz (Bessel filter, order=4). CHO-hERG Cells were held at −80 mV restingmembrane potential for 100 msec and at −50 mV for 100 msec (leaksubtraction), and depolarized to +20 mV for 4 sec (prepulse), followedby repolarization to −50 mV for 4 sec (test pulse) before returning tothe holding potential, −80 mV. The protocol was repeated every 20 sec.During each baseline and increased dose application period approximately10 voltage protocols were executed.

Fluidics: Cell suspension, compound samples, and Na-Ringer (wash) involumes of 5-15 μl were pipetted to the chips.

Data analysis: IC50 and Hill coefficient were estimated from best fitsto the experimental dose-response data by the Hill equation:Remaining current(%)=MaxI+((MinI−MaxI)/(1+((Conc./|C50)^Hill))) WhereMaxI=100, MinI=0

This fitting procedure returned values for the two variable parameters:an 1050 value and a Hill slope.

Certain Examples of the present invention were evaluated in the Q-patchclamp assay.

Biological Data

The results of the CDK4 and CDK1 enzymatic activity assays and the CDK4cellular assay are given in Table 1.

TABLE 1 Biochemical Cellular ppRb Normalized cellular Biochemical CDK4enzyme inhibition ppRb inhibition CDK1 enzyme Example IC50/uM IC50/uMIC50/uM IC50/uM 1 0.017 0.364 0.538 >15 2 0.005 0.066 0.084 >15 3 0.0010.019 to 0.026 0.029 to 0.033  4.2 to 5.143 4 0.004 0.009 0.01  7.065 50.008 to 0.016 0.115 0.117 >15 6 0.187 0.148 0.889 >15 7 0.021 0.1270.288 17.59 8 0.039 0.072 0.259 >15 9 <0.004  0.055 0.12  7.101 10<0.005 to 0.005  0.021 0.025 4.137 11 0.009 0.039 0.068 >15 12 0.0490.255 0.724 >15 13 0.006 0.065 0.145 8.439 14 0.019 0.133 0.371 >15 150.018 0.043 0.264 >15 16 0.015 0.092 0.233 >15 17 0.065 0.281 0.643 >1518 0.008 to 0.024 0.012 to 0.037 0.026 to 0.09  13.206 19 0.005 to 0.0080.054 to 0.055 0.064 to 0.116 >15 20 0.064 0.267 0.452 >15 21 0.0470.187 0.401 >15 22 0.062 to 0.083 0.086 to 0.513 0.086 to 0.817 >15 231.63  6.77  6.77  >15 24 0.049 0.266 0.272 >15 25 0.008 0.02  0.022 >1526 0.038 0.325 0.388 >15 27 0.046 0.194 0.201 >15 28 0.022 0.0630.069 >15 29 0.014 to 0.017 0.024 to 0.034  0.02 to 0.048 >15 30 0.088to 0.114 0.422 to 0.542 0.344 to 0.582 >15 31 0.069 to 0.081 0.252 to0.352 0.497 to 0.591 >15 32 0.015 to 0.021 0.131 0.212 >15 33 0.094 to0.144 0.377 to 0.919 0.43 to 1.3  >15 34 0.022 0.075 0.14  >15 35 0.0260.069 0.197 >15 36 0.003 0.023 0.028 12.965 37 <0.005 to 0.006  0.121 to0.301 0.288 to 0.438 >15 38 0.045 to 0.084 0.075 to 0.259 0.139 to0.783 >15 39 0.077 0.079 0.136 >15 40 0.036 to 0.052  0.04 to 0.0990.051 to 0.222 >15 41 0.015 to 0.017 0.112 to 0.228 0.132 to 0.415 >1542 0.015 0.086 0.241 >15 43 0.176 to 0.198 0.461 to 0.745 0.469 to1.28  >15 44 0.177 to 0.351  0.72 to 1.493 0.778 to ND  >15 45 0.014 to0.024 0.064 0.064 12.815 46 0.1  0.724 0.73  >15 47 0.03  0.3150.352 >15 48 0.024 0.152 0.229 >15 49 0.045 0.044 to 0.231 0.052 to0.431 >15 50 0.021 0.041 0.09  >15 51 0.023 0.028 0.06  >15 52 0.0270.021 to 0.047 0.045 to 0.053 >15 53 0.003 0.007 to 0.014 0.007 to0.027 >15 54 0.003 0.006 to 0.033 0.008 to 0.047 1.992 55 0.014 to 0.0360.031 to 0.112 0.035 to 0.164 >15 56 0.112 0.395 0.47  >15 571.566 >10     >10     >15 58 0.074 0.105 to 0.188 0.288 to 0.338 >15 590.008 2.5  >10     >15 60 0.019 0.021 0.047 >15 61 0.02  0.021 0.053 >1562 0.01  0.291 0.723 39.91 63 0.011 to 0.024 0.034 to 0.078  0.04 to0.242 >15 64 0.072 to 0.179 0.323 to 0.466 0.771 to 2.2  >15 65 0.0760.126 to 0.211 0.132 to 0.458 >15 66 0.004 to 0.007 0.038 0.041 >15 670.003 0.051 0.054 10.377 68 <0.005 to 0.008  0.266 0.712 >15 69 <0.005to 0.018  0.024 0.048 >15 70 0.039 0.117 0.18  >15 71 <0.005 to 0.006 0.031 0.056 12.731 72 0.013 0.048 0.112 >15 73 0.045 to 0.084 0.075 to0.259 0.139 to 0.783 >15 74 0.067 0.151 0.257 >15 75 0.047 0.0810.525 >15 76 0.021 0.16  0.216 >15 77 0.027 0.172 0.225 >15 78 0.0760.059 ND >15 79 0.042 0.030 0.117 >15 80 0.012 to 0.014 0.051 to 0.32 0.074 to 0.474 14.016 81 <0.005  0.003 0.004 3.812 82 0.004 0.005 0.0092.659 83 0.003 0.005 0.009 5.316 84 <0.005  0.007 to 0.017  0.01 to0.028 18.028 85 <0.005 to 0.007  0.005 to 0.017 0.009 to 0.021  8.977 to11.168 86 <0.005 to 0.006  0.008 to 0.017 0.013 to 0.014 20.621 87<0.005  0.005 to 0.008 0.006 to 0.015 4.14 88 <0.005 to 0.005  0.0070.011 2.511 89 0.003 <0.005 to 0.007  0.004 to 0.015 6.483 90 0.0050.009 to 0.034 0.014 to 0.056 >15 91 <0.005 to 0.007   0.01 to 0.0270.022 to 0.074 13.307 to 14.904 92 <0.005 to 0.007  0.005 to 0.02  0.019to 0.038 25.059 93 0.005 0.008 0.02  >15 94 0.041 to 0.044 0.025 to0.154 0.034 to 0.206 >15 95 0.007 0.004 to 0.02  0.021 to 0.065 13.974to 14.344 96 0.015 to 0.028 0.031 to 0.039 0.073 to 0.107 10.777 970.051 0.066 0.145 >15 98 0.016 to 0.098 0.136 to 0.266 0.291 to0.887 >15 99 0.071 0.463 0.618 >15 100 0.035 0.188 0.218 >15 101 0.02 0.058 0.11  >15 102 0.018 0.039 0.071 >15 103 0.017 0.024 to 0.072 0.064to 0.169 >15 104 0.02  0.029 0.064 >15 105 0.012 0.061 0.1  >15 1060.015 0.07  0.114 >15 107 0.009 0.013 to 0.049 0.037 to 0.114 >15 1080.013 0.061 0.069 >15 109 0.012 0.048 0.075 >15 110 0.008 0.0410.062 >15 111 0.041 0.371 0.452 9.17 112 0.011 to 0.034 0.092 0.231 >15113 0.017 to 0.021 0.177 to 0.205 0.204 to 0.245 11.561 to >15   1140.19  1.35  7.1  >15 115  0.02 to 0.051 0.135 to 0.306 0.369 to0.407 >15 116 0.11  0.604 0.605 >15 117 0.007 to 0.009  0.04 to 0.0670.051 to 0.082 >15 118 <0.005 to 0.014  0.034 to 0.147 0.047 to0.153 >15 119 0.012 0.026 to 0.047 0.072 to 0.083 >15 120 0.066 0.6771.03  >15 121 0.079 to 0.107 0.184 to 0.489 0.199 to 0.791 >15 122<0.005 to 0.01  0.009 0.014 >15 123 0.003 0.005 to 0.016 0.008 to 0.09929.281 124 0.023 0.158 0.261 >15 125 0.015 0.083 0.161 >15 126  0.01 to0.031 0.023 to 0.032 0.045 to 0.049 >15 127 0.005 0.119 to 0.917 0.247to 1.52  >15 128 0.009 0.081 0.14  >15 129 0.048 0.194 0.221 >15 1300.009 0.019 to 0.026 0.022 to 0.045 >15 131 0.004 0.014 0.024 >15 1320.019 0.021 to 0.05  0.028 to 0.047 >15 133 <0.005  0.005 0.007 13.338134 0.008 0.066 0.123 >15 135 0.007 0.019 0.038 >15 136 0.054 0.0770.218 >15 137 0.062 0.155 0.15  >15 138 0.106 1.6  ND >15 139 0.1140.605 0.638 >15 140 <0.005 to 0.006  0.005 to 0.009 0.011 to 0.018 >15141 0.045 0.024 0.034 >15 142 0.034 0.006 0.013 >15 143 0.044 0.1190.251 >15 144 0.019 0.031 0.049 >15 145 0.032 0.045 0.162 >15 146 0.6192.7  2.9  >15 147 0.027 0.257 0.31  >15

What is claimed is:
 1. A method for the treatment of a carcinoma withgenetic aberrations that activate CDK 4/6 kinase activity in a patientin need of treatment thereof comprising administration of an effectiveamount of a compound selected from the group consisting of:7-cyclopentyl-N,N-dimethyl-2-(5-((1R,6S)-9-methyl-4-oxo-3,9-diazabicyclo[4.2.1]nonan-3-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide;7-Cyclopentyl-2-[5-(3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide;7-Cyclopentyl-2-[5-((1R,6S)-4-oxo-3,9-diaza-bicyclo[4.2.1]non-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide;7-Cyclopentyl-2-[5-((1R,6S)-4-oxo-3,9-diaza-bicyclo[4.2.1]non-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid methylamide; and7-Cyclopentyl-2-[5-((1R,6S)-4-oxo-3,9-diaza-bicyclo[4.2.1]non-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid methylamide; or a pharmaceutically acceptable salt thereof.
 2. Themethod according to claim 1 wherein the compound is7-cyclopentyl-N,N-dimethyl-2-(5-((1R,6S)-9-methyl-4-oxo-3,9-diazabicyclo[4.2.1]nonan-3-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide;or a pharmaceutically acceptable salt thereof.
 3. The method accordingto claim 1 wherein the compound is7-Cyclopentyl-2-[5-(3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide; or a pharmaceutically acceptable salt thereof. 4.The method according to claim 1 wherein the compound is7-Cyclopentyl-2-[5-((1R,6S)-4-oxo-3,9-diaza-bicyclo[4.2.1]non-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide; or a pharmaceutically acceptable salt thereof. 5.The method according to claim 1 wherein the compound is7-Cyclopentyl-2-[5-((1R,6S)-4-oxo-3,9-diaza-bicyclo[4.2.1]non-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid methylamide; or a pharmaceutically acceptable salt thereof.
 6. Themethod according to claim 1 wherein the compound is7-cyclopentyl-2-[5-((1R,6S)-9-methyl-4-oxo-3,9-diaza-bicyclo[4.2.1]non-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid methylamide; or a pharmaceutically acceptable salt thereof.
 7. Themethod according to claim 1 wherein the carcinoma is mantle celllymphoma, multiple myeloma, breast cancer, squamous cell esophagealcancer, liposarcoma, melanoma, non small cell lung cancer or pancreaticcancer.
 8. The method according to claim 1 wherein the compound is7-cyclopentyl-N,N-dimethyl-2-(5-((1R,6S)-9-methyl-4-oxo-3,9-diazabicyclo[4.2.1]nonan-3-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide;or a pharmaceutically acceptable salt thereof.
 9. The method accordingto claim 7 wherein the compound is7-Cyclopentyl-2-[5-(3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide; or a pharmaceutically acceptable salt thereof. 10.The method according to claim 7 wherein the compound is7-Cyclopentyl-2-[5-((1R,6S)-4-oxo-3,9-diaza-bicyclo[4.2.1]non-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide; or a pharmaceutically acceptable salt thereof. 11.The method according to claim 7 wherein the compound is7-Cyclopentyl-2-[5-((1R,6S)-4-oxo-3,9-diaza-bicyclo[4.2.1]non-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid methylamide; or a pharmaceutically acceptable salt thereof.
 12. Themethod according to claim 7 wherein the compound is7-cyclopentyl-2-[5-((1R,6S)-9-methyl-4-oxo-3,9-diaza-bicyclo[4.2.1]non-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid methylamide; or a pharmaceutically acceptable salt thereof.
 13. Themethod according to claim 1 wherein the carcinoma is breast cancer ormelanoma.
 14. The method according to claim 13 wherein the compound is7-cyclopentyl-N,N-dimethyl-2-(5-((1R,6S)-9-methyl-4-oxo-3,9-diazabicyclo[4.2.1]nonan-3-yl)pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide;or a pharmaceutically acceptable salt thereof.
 15. The method accordingto claim 13 wherein the compound is7-Cyclopentyl-2-[5-(3,8-diaza-bicyclo[3.2.1]octane-3-carbonyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide; or a pharmaceutically acceptable salt thereof. 16.The method according to claim 13 wherein the compound is7-Cyclopentyl-2-[5-((1R,6S)-4-oxo-3,9-diaza-bicyclo[4.2.1]non-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid dimethylamide; or a pharmaceutically acceptable salt thereof. 17.The method according to claim 13 wherein the compound is7-Cyclopentyl-2-[5-((1R,6S)-4-oxo-3,9-diaza-bicyclo[4.2.1]non-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid methylamide; or a pharmaceutically acceptable salt thereof.
 18. Themethod according to claim 13 wherein the compound is7-cyclopentyl-2-[5-((1R,6S)-9-methyl-4-oxo-3,9-diaza-bicyclo[4.2.1]non-3-yl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylicacid methylamide; or a pharmaceutically acceptable salt thereof.